Journal articles on the topic 'Bioinformatics, metalloproteins, metal-binding proteins'
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Zhang, Yan, and Junge Zheng. "Bioinformatics of Metalloproteins and Metalloproteomes." Molecules 25, no. 15 (July 24, 2020): 3366. http://dx.doi.org/10.3390/molecules25153366.
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Trace metals are inorganic elements that are required for all organisms in very low quantities. They serve as cofactors and activators of metalloproteins involved in a variety of key cellular processes. While substantial effort has been made in experimental characterization of metalloproteins and their functions, the application of bioinformatics in the research of metalloproteins and metalloproteomes is still limited. In the last few years, computational prediction and comparative genomics of metalloprotein genes have arisen, which provide significant insights into their distribution, function, and evolution in nature. This review aims to offer an overview of recent advances in bioinformatic analysis of metalloproteins, mainly focusing on metalloprotein prediction and the use of different metals across the tree of life. We describe current computational approaches for the identification of metalloprotein genes and metal-binding sites/patterns in proteins, and then introduce a set of related databases. Furthermore, we discuss the latest research progress in comparative genomics of several important metals in both prokaryotes and eukaryotes, which demonstrates divergent and dynamic evolutionary patterns of different metalloprotein families and metalloproteomes. Overall, bioinformatic studies of metalloproteins provide a foundation for systematic understanding of trace metal utilization in all three domains of life.
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Andreini, Claudia, and Antonio Rosato. "Structural Bioinformatics and Deep Learning of Metalloproteins: Recent Advances and Applications." International Journal of Molecular Sciences 23, no. 14 (July 12, 2022): 7684. http://dx.doi.org/10.3390/ijms23147684.
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All living organisms require metal ions for their energy production and metabolic and biosynthetic processes. Within cells, the metal ions involved in the formation of adducts interact with metabolites and macromolecules (proteins and nucleic acids). The proteins that require binding to one or more metal ions in order to be able to carry out their physiological function are called metalloproteins. About one third of all protein structures in the Protein Data Bank involve metalloproteins. Over the past few years there has been tremendous progress in the number of computational tools and techniques making use of 3D structural information to support the investigation of metalloproteins. This trend has been boosted by the successful applications of neural networks and machine/deep learning approaches in molecular and structural biology at large. In this review, we discuss recent advances in the development and availability of resources dealing with metalloproteins from a structure-based perspective. We start by addressing tools for the prediction of metal-binding sites (MBSs) using structural information on apo-proteins. Then, we provide an overview of the methods for and lessons learned from the structural comparison of MBSs in a fold-independent manner. We then move to describing databases of metalloprotein/MBS structures. Finally, we summarizing recent ML/DL applications enhancing the functional interpretation of metalloprotein structures.
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Wang, Kai, Nan Lyu, Hongjuan Diao, Shujuan Jin, Tao Zeng, Yaoqi Zhou, and Ruibo Wu. "GM-DockZn: a geometry matching-based docking algorithm for zinc proteins." Bioinformatics 36, no. 13 (May 5, 2020): 4004–11. http://dx.doi.org/10.1093/bioinformatics/btaa292.
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Abstract Motivation Molecular docking is a widely used technique for large-scale virtual screening of the interactions between small-molecule ligands and their target proteins. However, docking methods often perform poorly for metalloproteins due to additional complexity from the three-way interactions among amino-acid residues, metal ions and ligands. This is a significant problem because zinc proteins alone comprise about 10% of all available protein structures in the protein databank. Here, we developed GM-DockZn that is dedicated for ligand docking to zinc proteins. Unlike the existing docking methods developed specifically for zinc proteins, GM-DockZn samples ligand conformations directly using a geometric grid around the ideal zinc-coordination positions of seven discovered coordination motifs, which were found from the survey of known zinc proteins complexed with a single ligand. Results GM-DockZn has the best performance in sampling near-native poses with correct coordination atoms and numbers within the top 50 and top 10 predictions when compared to several state-of-the-art techniques. This is true not only for a non-redundant dataset of zinc proteins but also for a homolog set of different ligand and zinc-coordination systems for the same zinc proteins. Similar superior performance of GM-DockZn for near-native-pose sampling was also observed for docking to apo-structures and cross-docking between different ligand complex structures of the same protein. The highest success rate for sampling nearest near-native poses within top 5 and top 1 was achieved by combining GM-DockZn for conformational sampling with GOLD for ranking. The proposed geometry-based sampling technique will be useful for ligand docking to other metalloproteins. Availability and implementation GM-DockZn is freely available at www.qmclab.com/ for academic users. Supplementary information Supplementary data are available at Bioinformatics online.
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Monette, Anne, and Andrew J. Mouland. "Zinc and Copper Ions Differentially Regulate Prion-Like Phase Separation Dynamics of Pan-Virus Nucleocapsid Biomolecular Condensates." Viruses 12, no. 10 (October 18, 2020): 1179. http://dx.doi.org/10.3390/v12101179.
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Liquid-liquid phase separation (LLPS) is a rapidly growing research focus due to numerous demonstrations that many cellular proteins phase-separate to form biomolecular condensates (BMCs) that nucleate membraneless organelles (MLOs). A growing repertoire of mechanisms supporting BMC formation, composition, dynamics, and functions are becoming elucidated. BMCs are now appreciated as required for several steps of gene regulation, while their deregulation promotes pathological aggregates, such as stress granules (SGs) and insoluble irreversible plaques that are hallmarks of neurodegenerative diseases. Treatment of BMC-related diseases will greatly benefit from identification of therapeutics preventing pathological aggregates while sparing BMCs required for cellular functions. Numerous viruses that block SG assembly also utilize or engineer BMCs for their replication. While BMC formation first depends on prion-like disordered protein domains (PrLDs), metal ion-controlled RNA-binding domains (RBDs) also orchestrate their formation. Virus replication and viral genomic RNA (vRNA) packaging dynamics involving nucleocapsid (NC) proteins and their orthologs rely on Zinc (Zn) availability, while virus morphology and infectivity are negatively influenced by excess Copper (Cu). While virus infections modify physiological metal homeostasis towards an increased copper to zinc ratio (Cu/Zn), how and why they do this remains elusive. Following our recent finding that pan-retroviruses employ Zn for NC-mediated LLPS for virus assembly, we present a pan-virus bioinformatics and literature meta-analysis study identifying metal-based mechanisms linking virus-induced BMCs to neurodegenerative disease processes. We discover that conserved degree and placement of PrLDs juxtaposing metal-regulated RBDs are associated with disease-causing prion-like proteins and are common features of viral proteins responsible for virus capsid assembly and structure. Virus infections both modulate gene expression of metalloproteins and interfere with metal homeostasis, representing an additional virus strategy impeding physiological and cellular antiviral responses. Our analyses reveal that metal-coordinated virus NC protein PrLDs initiate LLPS that nucleate pan-virus assembly and contribute to their persistence as cell-free infectious aerosol droplets. Virus aerosol droplets and insoluble neurological disease aggregates should be eliminated by physiological or environmental metals that outcompete PrLD-bound metals. While environmental metals can control virus spreading via aerosol droplets, therapeutic interference with metals or metalloproteins represent additional attractive avenues against pan-virus infection and virus-exacerbated neurological diseases.
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Aramini, James M., and Hans J. Vogel. "Quadrupolar metal ion NMR studies of metalloproteins." Biochemistry and Cell Biology 76, no. 2-3 (May 1, 1998): 210–22. http://dx.doi.org/10.1139/o98-037.
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We present a summary of the quadrupolar metal ion NMR studies of metalloproteins conducted in our laboratory in recent years. The approaches we employ can be subdivided into two categories: (i) the use of low-frequency metal nuclei to probe metal ion binding sites in small proteins, exemplified by 43Ca NMR studies of alpha-lactalbumins and calcium-binding lysozymes, and (ii) the novel detection of the central transition of half-integer quadrupolar nuclei of moderate frequency bound to large metalloproteins, typified by 27Al, 45Sc, 69,71Ga, and 51V NMR studies of the transferrins. We highlight the chemical information regarding the nature of metal ion binding sites that can be obtained from this technique and emphasize the salient parameters that an investigator must consider to successfully apply quadrupolar NMR to the study of biological macromolecules.Key words: quadrupolar NMR, metalloproteins, transferrins.
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Dudev, Todor, Luis Manuel Frutos, and Obis Castaño. "How mechanical forces can modulate the metal affinity and selectivity of metal binding sites in proteins." Metallomics 12, no. 3 (2020): 363–70. http://dx.doi.org/10.1039/c9mt00283a.
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Arnesano, Fabio, Lucia Banci, and Mario Piccioli. "NMR structures of paramagnetic metalloproteins." Quarterly Reviews of Biophysics 38, no. 2 (May 2005): 167–219. http://dx.doi.org/10.1017/s0033583506004161.
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1. Introduction 1681.1 Genomic annotation of metalloproteins 1681.2 Why NMR structures? 1681.3 Why paramagnetic metalloproteins? 1692. General theory 1702.1 Nuclear and electron spins 1702.2 Hyperfine coupling 1712.3 The effect of the hyperfine coupling on the NMR shift: the hyperfine shift 1732.4 The effect of the hyperfine coupling on nuclear relaxation 1742.5 Interplay between electron spin properties and features of the NMR spectra 1783. Paramagnetism-based structural restraints 1803.1 Contact shifts and relaxation rates as restraints 1813.2 Locating the metal ion within the protein frame: pseudocontact shifts 1843.3 Cross-correlation rates 1863.4 Residual dipolar couplings 1883.5 Interplay between different restraints 1904. NMR without1H detection 1914.1 The protocol for 13C-detected protonless assignment of backbone and side-chains 1944.2 Protonless heteronuclear NMR experiments tailored to paramagnetic systems 1965. The use of lanthanides as paramagnetic probes 1986. The case of Cu(II) proteins 2027. Perspectives 2088. Acknowledgments 2099. References 209Metalloproteins represent a large share of the proteome and many of them contain paramagnetic metal ions. The knowledge, at atomic resolution, of their structure in solution is important to understand processes in which they are involved, such as electron transfer mechanisms, enzymatic reactions, metal homeostasis and metal trafficking, as well as interactions with their partners. Formerly considered as unfeasible, the first structure in solution by nuclear magnetic resonance (NMR) of a paramagnetic protein was obtained in 1994. Methodological and instrumental advancements pursued over the last decade are such that NMR structure of paramagnetic proteins may be now routinely obtained. We focus here on approaches and problems related to the structure determination of paramagnetic proteins in solution through NMR spectroscopy. After a survey of the background theory, we show how the effects produced by the presence of a paramagnetic metal ion on the NMR parameters, which are in many cases deleterious for the detection of NMR spectra, can be overcome and turned into an additional source of structural restraints. We also briefly address features and perspectives given by the use of 13C-detected protonless NMR spectroscopy for proteins in solution. The structural information obtained through the exploitation of a paramagnetic center are discussed for some Cu2+-binding proteins and for Ca2+-binding proteins, where the replacement of a diamagnetic metal ion with suitable paramagnetic metal ions suggests novel approaches to the structural characterization of proteins containing diamagnetic and NMR-silent metal ions.
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Yu, Yue, Ruobing Wang, and Ruijie D. Teo. "Machine Learning Approaches for Metalloproteins." Molecules 27, no. 4 (February 14, 2022): 1277. http://dx.doi.org/10.3390/molecules27041277.
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Metalloproteins are a family of proteins characterized by metal ion binding, whereby the presence of these ions confers key catalytic and ligand-binding properties. Due to their ubiquity among biological systems, researchers have made immense efforts to predict the structural and functional roles of metalloproteins. Ultimately, having a comprehensive understanding of metalloproteins will lead to tangible applications, such as designing potent inhibitors in drug discovery. Recently, there has been an acceleration in the number of studies applying machine learning to predict metalloprotein properties, primarily driven by the advent of more sophisticated machine learning algorithms. This review covers how machine learning tools have consolidated and expanded our comprehension of various aspects of metalloproteins (structure, function, stability, ligand-binding interactions, and inhibitors). Future avenues of exploration are also discussed.
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Carugo, Oliviero. "Metalloproteins: metal binding predicted on the basis of the amino acid sequence." Journal of Applied Crystallography 41, no. 1 (January 16, 2008): 104–9. http://dx.doi.org/10.1107/s0021889807065235.
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A protein sequence is often insufficient for knowledge of the chemical formula and the properties of the mature molecule that perform its function. Post-translational modifications are very common and most of them cannot be predicted on the basis of the protein sequence alone. A very common chemical modification of proteins that is not directly encoded by a single gene is the complexation with metal cations. Here it is shown that the uptake of metal ions (calcium, cobalt, copper, iron, magnesium, manganese, nickel or zinc) by proteins can be predicted on the basis of the amino acid composition, by using a mixture of several simplified amino acid alphabets and by employing machine learning methods, with 70–90% accuracy, depending on the type of metal. Not only is it possible to predict if a protein requires a certain metal ion but it is also possible to discriminate amongst various metal species. These results are likely to be useful in structural proteomics, by improving the experiment success rate, and in comparative genomics, where it is interesting to compare metal-ion contents in different organisms. It is particularly important that these predictions can be made when homology-based annotations are impossible.
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Öz, Gülin, Dean L. Pountney, and Ian M. Armitage. "NMR spectroscopic studies of I = 1/2 metal ions in biological systems." Biochemistry and Cell Biology 76, no. 2-3 (May 1, 1998): 223–34. http://dx.doi.org/10.1139/o98-059.
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This article reviews the use of nuclear magnetic resonance methods of spin 1/2 metal nuclei to probe the metal binding site(s) in a variety of metalloproteins. The majority of the studies have involved native Zn(II) and Ca(II) metalloproteins where there has been isostructural substitution of these metal ions with the I = 1/2 111/113Cd(II) ion. Also included are recent studies that have utilized the 109Ag(I) ion to probe Cu(I) sites in yeast metallothionein and 199Hg(II) as a probe of the metal binding sites in mercury resistance proteins. Pertinent aspects for the optimal execution of these experiments along with the procedures for the metal substitution reactions are discussed together with the presentation of a 113Cd chemical shift correlation map with ligand type and coordination number. Specific examples of protein systems studied using the 111/113Cd and 109Ag nuclei include the metallothionein superfamily of Zn(II)- and Cu(I)-binding proteins from mammalian, invertebrate, and yeast systems. In addition to the structural features revealed by these metal ion nuclear magnetic resonance studies, important new information is frequently provided about the dynamics at the active-site metal ion. In an effort for completeness, other less frequently used spin 1/2 metal nuclei are mentioned.Key words: metallothionein, 111/113Cd, 199Hg, 109Ag, 57Fe, 205Tl, 195Pt, 207Pb, 119Sn, nuclear magnetic resonance.
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Nguyen, Kiet T., Kristina Piastro, and Keith M. Derbyshire. "LpqM, a Mycobacterial Lipoprotein-Metalloproteinase, Is Required for Conjugal DNA Transfer in Mycobacterium smegmatis." Journal of Bacteriology 191, no. 8 (February 20, 2009): 2721–27. http://dx.doi.org/10.1128/jb.00024-09.
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ABSTRACT We have previously described a novel conjugal DNA transfer process that occurs in Mycobacterium smegmatis. To identify donor genes required for transfer, we have performed a transposon mutagenesis screen; we report here that LpqM, a putative lipoprotein-metalloproteinase, is essential for efficient DNA transfer. Bioinformatic analyses predict that LpqM contains a signal peptide necessary for the protein's targeting to the cell envelope and a metal ion binding motif, the likely catalytic site for protease activity. Using targeted mutagenesis, we demonstrate that each of these motifs is necessary for DNA transfer and that LpqM is located in the cell envelope. The requirement for transfer is specific to the donor strain; an lpqM knockout mutant in the recipient is still proficient in transfer assays. The activity of LpqM is conserved among mycobacteria; homologues from both Mycobacterium tuberculosis and Mycobacterium avium can complement lpqM donor mutants, suggesting that the homologues recognize and process similar proteins. Lipoproteins constitute a significant proportion of the mycobacterial cell wall, but despite their abundance, very few have been assigned an activity. We discuss the potential role of LpqM in DNA transfer and the implications of the conservation of LpqM activity in M. tuberculosis.
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LIN, CHIN-TENG, KEN-LI LIN, CHIH-HSIEN YANG, I.-FANG CHUNG, CHUEN-DER HUANG, and YUH-SHYONG YANG. "PROTEIN METAL BINDING RESIDUE PREDICTION BASED ON NEURAL NETWORKS." International Journal of Neural Systems 15, no. 01n02 (February 2005): 71–84. http://dx.doi.org/10.1142/s0129065705000116.
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Over one-third of protein structures contain metal ions, which are the necessary elements in life systems. Traditionally, structural biologists were used to investigate properties of metalloproteins (proteins which bind with metal ions) by physical means and interpreting the function formation and reaction mechanism of enzyme by their structures and observations from experiments in vitro. Most of proteins have primary structures (amino acid sequence information) only; however, the 3-dimension structures are not always available. In this paper, a direct analysis method is proposed to predict the protein metal-binding amino acid residues from its sequence information only by neural networks with sliding window-based feature extraction and biological feature encoding techniques. In four major bulk elements (Calcium, Potassium, Magnesium, and Sodium), the metal-binding residues are identified by the proposed method with higher than 90% sensitivity and very good accuracy under 5-fold cross validation. With such promising results, it can be extended and used as a powerful methodology for metal-binding characterization from rapidly increasing protein sequences in the future.
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Chipinda, Itai, Justin M. Hettick, and Paul D. Siegel. "Haptenation: Chemical Reactivity and Protein Binding." Journal of Allergy 2011 (June 30, 2011): 1–11. http://dx.doi.org/10.1155/2011/839682.
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Low molecular weight chemical (LMW) allergens are commonly referred to as haptens. Haptens must complex with proteins to be recognized by the immune system. The majority of occupationally related haptens are reactive, electrophilic chemicals, or are metabolized to reactive metabolites that form covalent bonds with nucleophilic centers on proteins. Nonelectrophilic protein binding may occur through disulfide exchange, coordinate covalent binding onto metal ions on metalloproteins or of metal allergens, themselves, to the major histocompatibility complex. Recent chemical reactivity kinetic studies suggest that the rate of protein binding is a major determinant of allergenic potency; however, electrophilic strength does not seem to predict the ability of a hapten to skew the response between Th1 and Th2. Modern proteomic mass spectrometry methods that allow detailed delineation of potential differences in protein binding sites may be valuable in predicting if a chemical will stimulate an immediate or delayed hypersensitivity. Chemical aspects related to both reactivity and protein-specific binding are discussed.
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Lin, Ying-Wu. "Uranyl Binding to Proteins and Structural-Functional Impacts." Biomolecules 10, no. 3 (March 16, 2020): 457. http://dx.doi.org/10.3390/biom10030457.
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The widespread use of uranium for civilian purposes causes a worldwide concern of its threat to human health due to the long-lived radioactivity of uranium and the high toxicity of uranyl ion (UO22+). Although uranyl–protein/DNA interactions have been known for decades, fewer advances are made in understanding their structural-functional impacts. Instead of focusing only on the structural information, this article aims to review the recent advances in understanding the binding of uranyl to proteins in either potential, native, or artificial metal-binding sites, and the structural-functional impacts of uranyl–protein interactions, such as inducing conformational changes and disrupting protein-protein/DNA/ligand interactions. Photo-induced protein/DNA cleavages, as well as other impacts, are also highlighted. These advances shed light on the structure-function relationship of proteins, especially for metalloproteins, as impacted by uranyl–protein interactions. It is desired to seek approaches for biological remediation of uranyl ions, and ultimately make a full use of the double-edged sword of uranium.
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Dudev, Todor. "How Theoretical Evaluations Can Generate Guidelines for Designing/Engineering Metalloproteins with Desired Metal Affinity and Selectivity." Molecules 28, no. 1 (December 28, 2022): 249. http://dx.doi.org/10.3390/molecules28010249.
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Almost half of all known proteins contain metal co-factors. Crucial for the flawless performance of a metalloprotein is the selection with high fidelity of the cognate metal cation from the surrounding biological fluids. Therefore, elucidating the factors controlling the metal binding and selectivity in metalloproteins is of particular significance. The knowledge thus acquired not only contributes to better understanding of the intimate mechanism of these events but, also, significantly enriches the researcher’s toolbox that could be used in designing/engineering novel metalloprotein structures with pre-programmed properties. A powerful tool in aid of deciphering the physical principles behind the processes of metal recognition and selectivity is theoretical modeling of metal-containing biological structures. This review summarizes recent findings in the field with an emphasis on elucidating the major factors governing these processes. The results from theoretical evaluations are discussed. It is the hope that the physical principles evaluated can serve as guidelines in designing/engineering of novel metalloproteins of interest to both science and industry.
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Braga, Camila Pereira, José Cavalcante Souza Vieira, Ryan A. Grove, Cory H. T. Boone, Aline de Lima Leite, Marília Afonso Rabelo Buzalaf, Ana Angélica Henrique Fernandes, Jiri Adamec, and Pedro de Magalhaes Padilha. "A proteomic approach to identify metalloproteins and metal-binding proteins in liver from diabetic rats." International Journal of Biological Macromolecules 96 (March 2017): 817–32. http://dx.doi.org/10.1016/j.ijbiomac.2016.12.073.
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Wilson, Corey J., David Apiyo, and Pernilla Wittung-Stafshede. "Role of cofactors in metalloprotein folding." Quarterly Reviews of Biophysics 37, no. 3-4 (November 2004): 285–314. http://dx.doi.org/10.1017/s003358350500404x.
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Metals are commonly found as natural constituents of proteins. Since many such metals can interact specifically with their corresponding unfolded proteins in vitro, cofactor-binding prior to polypeptide folding may be a biological path to active metalloproteins. By interacting with the unfolded polypeptide, the metal may create local structure that initiates and directs the polypeptide-folding process. Here, we review recent literature that addresses the involvement of metals in protein-folding reactions in vitro. To date, the best characterized systems are simple one such as blue-copper proteins, heme-binding proteins, iron-sulfur-cluster proteins and synthetic metallopeptides. Taken together, the available data demonstrates that metals can play diverse roles: it is clear that many cofactors bind before polypeptide folding and influence the reaction; yet, some do not bind until a well-structured active site is formed. The significance of characterizing the effects of metals on protein conformational changes is underscored by the many human diseases that are directly linked to anomalous protein–metal interactions.
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Watly, Joanna, Aleksandra Hecel, Paulina Kolkowska, Henryk Kozlowski, and Magdalena Rowinska-Zyrek. "Poly-Xaa Sequences in Proteins - Biological Role and Interactions with Metal Ions: Chemical and Medical Aspects." Current Medicinal Chemistry 25, no. 1 (January 22, 2018): 22–48. http://dx.doi.org/10.2174/0929867324666170428104928.
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Background: The understanding of the bioinorganic and coordination chemistry of metalloproteins containing unusual poly-Xaa sequences, in which a single amino acid is repeated consecutively, is crucial for describing their metal binding-structure-function relationship, and therefore also crucial for understanding their medicinal potential. To the best of our knowledge, this is the first systematic review on metal complexes with polyXaa sequences. Methods: We performed a thorough search of high quality peer reviewed literature on poly-Xaa type of sequences in proteins, focusing on their biological importance and on their interactions with metal ions. Results: 228 papers were included in the review. More than 70% of them discussed the role of metal complexes with the studied types of sequences. In this work, we showed numerous medically important and chemically fascinating examples of possible ‘poly-Xaa' metal binding sequences. Conclusion: Poly-Xaa sequences, in which a single amino acid is repeated consecutively, are often not only tempting binding sites for metal ions, but very often, together with the bound metal, serve as structure determinants for entire proteins. This, in turn, can have consequences for the whole organism. Such sequences in bacterial metal chaperones can be a possible target for novel, antimicrobial therapeutics.
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Wang, Michael S., Kenric J. Hoegler, and Michael H. Hecht. "Unevolved De Novo Proteins Have Innate Tendencies to Bind Transition Metals." Life 9, no. 1 (January 9, 2019): 8. http://dx.doi.org/10.3390/life9010008.
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Life as we know it would not exist without the ability of protein sequences to bind metal ions. Transition metals, in particular, play essential roles in a wide range of structural and catalytic functions. The ubiquitous occurrence of metalloproteins in all organisms leads one to ask whether metal binding is an evolved trait that occurred only rarely in ancestral sequences, or alternatively, whether it is an innate property of amino acid sequences, occurring frequently in unevolved sequence space. To address this question, we studied 52 proteins from a combinatorial library of novel sequences designed to fold into 4-helix bundles. Although these sequences were neither designed nor evolved to bind metals, the majority of them have innate tendencies to bind the transition metals copper, cobalt, and zinc with high nanomolar to low-micromolar affinity.
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Moulis, Jean-Marc. "Cellular Dynamics of Transition Metal Exchange on Proteins: A Challenge but a Bonanza for Coordination Chemistry." Biomolecules 10, no. 11 (November 21, 2020): 1584. http://dx.doi.org/10.3390/biom10111584.
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Transition metals interact with a large proportion of the proteome in all forms of life, and they play mandatory and irreplaceable roles. The dynamics of ligand binding to ions of transition metals falls within the realm of Coordination Chemistry, and it provides the basic principles controlling traffic, regulation, and use of metals in cells. Yet, the cellular environment stands out against the conditions prevailing in the test tube when studying metal ions and their interactions with various ligands. Indeed, the complex and often changing cellular environment stimulates fast metal–ligand exchange that mostly escapes presently available probing methods. Reducing the complexity of the problem with purified proteins or in model organisms, although useful, is not free from pitfalls and misleading results. These problems arise mainly from the absence of the biosynthetic machinery and accessory proteins or chaperones dealing with metal / metal groups in cells. Even cells struggle with metal selectivity, as they do not have a metal-directed quality control system for metalloproteins, and serendipitous metal binding is probably not exceptional. The issue of metal exchange in biology is reviewed with particular reference to iron and illustrating examples in patho-physiology, regulation, nutrition, and toxicity.
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Al Bratty, Mohammed, Hassan A. Alhazmi, Sadique A. Javed, Zia Ur Rehman, Asim Najmi, and Karam A. El-Sharkawy. "Rapid Screening and Estimation of Binding Constants for Interactions of Fe3+ with Two Metalloproteins, Apotransferrin and Transferrin, Using Affinity Mode of Capillary Electrophoresis." Journal of Spectroscopy 2021 (November 19, 2021): 1–10. http://dx.doi.org/10.1155/2021/6987454.
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The interaction behavior of Fe3+ with transferrin and apotransferrin (iron-free form) was investigated in this study using affinity capillary electrophoresis. Change in the mass and charge of protein upon binding to the metal ion in the capillary tube led to variation in its migration time and was used to measure the noncovalent binding interactions by fast screening method. Acetanilide was used as the electroosmotic flow (EOF) marker to avoid possible errors due to the change in EOF during the experiment. The binding results were calculated from the mobility ratios of protein (Ri) and EOF marker (Rf) using the formula (Ri − Rf)/Rf or ∆R/Rf. For more comprehensive understanding, the kinetics of the interaction was studied and binding constants were calculated. Results showed that the Fe3+ displayed insignificant interaction with both proteins at lower metal ion concentrations (5–25 μmol/mL). However, transferrin exhibited significant interactions with the metal ion at 50 and 100 μmol/mL (ΔR/Rf = 0.0114 and 0.0201, resp.) concentrations and apotransferrin showed strong binding interactions (ΔR/Rf = −0.0254 and 0.0205, resp.) at relatively higher Fe3+ concentrations of 100 and 250 μmol/mL. The binding constants of 18.968 mmol−1 and −13.603 mmol−1 were recorded for Fe3+ interaction with transferrin and apotransferrin, respectively, showing significant interactions. Different binding patterns of Fe3+ with both proteins might be attributed to the fact that the iron-binding sites in transferrin have already been occupied, which was not the case in apotransferrin. The present study may be used as a reference for the investigation of protein-metal ion, drug-protein, drug-metal ion, and enzyme-metal ion interactions and may be helpful to provide preliminary insight into the new metal-based drug development.
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Lippi, M., A. Passerini, M. Punta, B. Rost, and P. Frasconi. "MetalDetector: a web server for predicting metal-binding sites and disulfide bridges in proteins from sequence." Bioinformatics 24, no. 18 (July 16, 2008): 2094–95. http://dx.doi.org/10.1093/bioinformatics/btn371.
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Levy, Mark A., Yu-Hwai Tsai, Andrew Reaume, and Tammy M. Bray. "Cellular response of antioxidant metalloproteins in Cu/Zn SOD transgenic mice exposed to hyperoxia." American Journal of Physiology-Lung Cellular and Molecular Physiology 281, no. 1 (July 1, 2001): L172—L182. http://dx.doi.org/10.1152/ajplung.2001.281.1.l172.
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Ceruloplasmin, metallothionein, and ferritin are metal-binding proteins with potential antioxidant activity. Despite evidence that they are upregulated in pulmonary tissue after oxidative stress, little is known regarding their influence on trace metal homeostasis. In this study, we have used copper- and zinc-containing superoxide dismutase (Cu/Zn SOD) transgenic-overexpressing and gene knockout mice and hyperoxia to investigate the effects of chronic and acute oxidative stress on the expression of these metalloproteins and to identify their influence on copper, zinc, and iron homeostasis. We found that the oxidative stress-mediated induction of ceruloplasmin and metallothionein in the lung had no effect on tissue levels of copper, iron, or zinc. However, Cu/Zn SOD expression had a marked influence on hepatic copper and iron as well as circulating copper homeostasis. These results suggest that ceruloplasmin and metallothionein may function as antioxidants independent of their role in trace metal homeostasis and that Cu/Zn SOD functions in copper homeostasis via mechanisms distinct from its superoxide scavenging properties.
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Saponja, Jillian A., and Hans J. Vogel. "Quadrupolar central transition (QCT) and 13C NMR competition studies of metal ion binding to ovotransferrin." Canadian Journal of Chemistry 89, no. 7 (July 2011): 779–88. http://dx.doi.org/10.1139/v11-019.
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The transferrins are a family of relatively large bilobal proteins that play a major role in the transport of Fe3+, as well as several other physiological and nonphysiological metal ions. Transferrins can also act as antimicrobial agents, by tightly sequestering iron and making it unavailable for bacterial growth. Using a combination of quadrupolar central transition (QCT) metal ion NMR (27Al, 45Sc, 51V, and 71Ga) and 13C NMR, the binding and displacement of a variety of metal ions to ovotransferrin was studied through direct metal ion competition experiments. The metal ions investigated (Al3+, Co3+, Fe3+, Ga3+, In3+, Sc3+, Y3+, and VO2+) were of differing ionic radius and charge, thus allowing for an assessment of how these factors contribute to metal ion affinity. The competition for the N- and C-terminal metal ion binding sites on ovotransferrin was directly followed by metal ion QCT NMR. Moreover, 13C NMR was used to study the two protein-bound synergistic anions (13C-labeled carbonate), whose chemical shifts are distinct and dependent on the bound metal ion that is present in the binding sites. The observed order of decreasing affinity for the metal ions studied was Fe3+ ≈ In3+ ≥ Sc3+ ≥ Ga3+ > Al3+ > VO2+ > Y3+ ≥ Co3+. These results illustrate how a combination of multinuclear solution NMR methods can provide unique insights into the ligand binding properties of larger metalloproteins.
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Chasapis, Christos T. "Interactions between metal binding viral proteins and human targets as revealed by network-based bioinformatics." Journal of Inorganic Biochemistry 186 (September 2018): 157–61. http://dx.doi.org/10.1016/j.jinorgbio.2018.06.012.
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Berniyanti, Titiek, Alexander Patera Nugraha, Novi Nurul Hidayati, Viol Dhea Kharisma, Albertus Putera Nugraha, and Tengku Natasha Eleena Binti Tengku Ahmad Noor. "Computational study of Cu2+, Fe2+, Mn2+, Mn3+, Fe3+, CrO42-, Si4+, and Hg+ binding sites identification on cytokines to predict dental metal allergy: An in silico study." Journal of Pharmacy & Pharmacognosy Research 10, no. 4 (July 1, 2022): 687–94. http://dx.doi.org/10.56499/jppres22.1372_10.4.687.
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Context: Metal allergy is a general term to describe allergic diseases due to the release of metal ion reactions in the body which are mediated by T cells and involve inflammatory cytokines that can cause morbidity and mortality. Molecular docking is an analysis that can be used to assess the interaction of ligand bonds with target proteins that are used to predict metal allergies caused by metal ions that stimulate cytokines. Aims: To analyze the binding sites of Cu2+, Fe2+, Mn2+, Mn3+, Fe3+, CrO42-, Si4+, and Hg+ ions on cytokines to predict dental metal allergy through a bioinformatics approach, in silico. Methods: Metal ion particles consisting of Cu2+, Fe2+, Mn2+, Mn3+, Fe3+, CrO42-, Si4+, and Hg+ were predicted to bind tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin (IL) IL-1b, IL-2, IL-4, IL-10, IL-13, IL-17, IL-23, and IL-33 act as target proteins were examined. Results: The blind docking simulation succeeded in identifying the comparison of the binding activity of metal ion particles on cytokines target proteins. The docking simulation results show that the metal ion with the most negative binding affinity value binds to the IL-17 protein. Conclusions: Metal ion particles consisting of Cu2+, Fe2+, Mn2+, Mn3+, Fe3+, CrO42-, Si4+, and Hg+ have the most negative binding affinity values for binding to IL-17 protein, which can cause allergic reactions predicted by molecular docking, in silico.
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Zhang, Tuo, Eziz Kuliyev, Dexin Sui, and Jian Hu. "The histidine-rich loop in the extracellular domain of ZIP4 binds zinc and plays a role in zinc transport." Biochemical Journal 476, no. 12 (June 28, 2019): 1791–803. http://dx.doi.org/10.1042/bcj20190108.
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Abstract The Zrt-/Irt-like protein (ZIP) family mediates zinc influx from extracellular space or intracellular vesicles/organelles, playing a central role in systemic and cellular zinc homeostasis. Out of the 14 family members encoded in human genome, ZIP4 is exclusively responsible for zinc uptake from dietary food and dysfunctional mutations of ZIP4 cause a life-threatening genetic disorder, Acrodermatitis Enteropathica (AE). About half of the missense AE-causing mutations occur within the large N-terminal extracellular domain (ECD), and our previous study has shown that ZIP4–ECD is crucial for optimal zinc uptake but the underlying mechanism has not been clarified. In this work, we examined zinc binding to the isolated ZIP4–ECD from Pteropus Alecto (black fruit bat) and located zinc-binding sites with a low micromolar affinity within a histidine-rich loop ubiquitously present in ZIP4 proteins. Zinc binding to this protease-susceptible loop induces a small and highly localized structural perturbation. Mutagenesis and functional study on human ZIP4 by using an improved cell-based zinc uptake assay indicated that the histidine residues within this loop are not involved in preselection of metal substrate but play a role in promoting zinc transport. The possible function of the histidine-rich loop as a metal chaperone facilitating zinc binding to the transport site and/or a zinc sensor allosterically regulating the transport machinery was discussed. This work helps to establish the structure/function relationship of ZIP4 and also sheds light on other metal transporters and metalloproteins with clustered histidine residues.
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Li, Dandan, Tengbing He, Muhammad Saleem, and Guandi He. "Metalloprotein-Specific or Critical Amino Acid Residues: Perspectives on Plant-Precise Detoxification and Recognition Mechanisms under Cadmium Stress." International Journal of Molecular Sciences 23, no. 3 (February 3, 2022): 1734. http://dx.doi.org/10.3390/ijms23031734.
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Cadmium (Cd) pollution in cultivated land is caused by irresistible geological factors and human activities; intense diffusion and migration have seriously affected the safety of food crops. Plants have evolved mechanisms to control excessive influx of Cd in the environment, such as directional transport, chelation and detoxification. This is done by some specific metalloproteins, whose key amino acid motifs have been investigated by scientists one by one. The application of powerful cell biology, crystal structure science, and molecular probe targeted labeling technology has identified a series of protein families involved in the influx, transport and detoxification of the heavy metal Cd. This review summarizes them as influx proteins (NRAMP, ZIP), chelating proteins (MT, PDF), vacuolar proteins (CAX, ABCC, MTP), long-distance transport proteins (OPT, HMA) and efflux proteins (PCR, ABCG). We selected representative proteins from each family, and compared their amino acid sequence, motif structure, subcellular location, tissue specific distribution and other characteristics of differences and common points, so as to summarize the key residues of the Cd binding target. Then, we explain its special mechanism of action from the molecular structure. In conclusion, this review is expected to provide a reference for the exploration of key amino acid targets of Cd, and lay a foundation for the intelligent design and breeding of crops with high/low Cd accumulation.
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Lee, Myungwoon, Tuo Wang, Olga V. Makhlynets, Yibing Wu, Nicholas F. Polizzi, Haifan Wu, Pallavi M. Gosavi, et al. "Zinc-binding structure of a catalytic amyloid from solid-state NMR." Proceedings of the National Academy of Sciences 114, no. 24 (May 31, 2017): 6191–96. http://dx.doi.org/10.1073/pnas.1706179114.
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Throughout biology, amyloids are key structures in both functional proteins and the end product of pathologic protein misfolding. Amyloids might also represent an early precursor in the evolution of life because of their small molecular size and their ability to self-purify and catalyze chemical reactions. They also provide attractive backbones for advanced materials. When β-strands of an amyloid are arranged parallel and in register, side chains from the same position of each chain align, facilitating metal chelation when the residues are good ligands such as histidine. High-resolution structures of metalloamyloids are needed to understand the molecular bases of metal–amyloid interactions. Here we combine solid-state NMR and structural bioinformatics to determine the structure of a zinc-bound metalloamyloid that catalyzes ester hydrolysis. The peptide forms amphiphilic parallel β-sheets that assemble into stacked bilayers with alternating hydrophobic and polar interfaces. The hydrophobic interface is stabilized by apolar side chains from adjacent sheets, whereas the hydrated polar interface houses the Zn2+-binding histidines with binding geometries unusual in proteins. Each Zn2+ has two bis-coordinated histidine ligands, which bridge adjacent strands to form an infinite metal–ligand chain along the fibril axis. A third histidine completes the protein ligand environment, leaving a free site on the Zn2+ for water activation. This structure defines a class of materials, which we call metal–peptide frameworks. The structure reveals a delicate interplay through which metal ions stabilize the amyloid structure, which in turn shapes the ligand geometry and catalytic reactivity of Zn2+.
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Maret, Wolfgang. "Zinc proteomics and the annotation of the human zinc proteome." Pure and Applied Chemistry 80, no. 12 (January 1, 2008): 2679–87. http://dx.doi.org/10.1351/pac200880122679.
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Sequence databases can be searched for homologies of zinc coordination motifs with characteristic ligand signatures. Ensuing predictions that 3-10 % of the human genes encodes zinc proteins are most remarkable. But they seem conservative when considering that database mining cannot discover new signatures or coordination environments that employ nonsequential binding of ligands and sulfur-ligand bridges. Predictions also fall short for zinc/protein interactions at protein interfaces and for inhibitory zinc sites. Zinc ions transiently target proteins that are not known to be zinc proteins, adding a hitherto unrecognized dimension to the human zinc proteome. Predicted zinc sites need to be verified experimentally. The metal can be absent or sites may bind metal ions other than zinc because protein coordination environments do not have absolute specificity for zinc. The metaphor of the "galvanization of biology" continues to gain prominence in terms of the sheer number of approximately 3000 human zinc proteins and their annotation with new functions. Clearly, description of zinc proteomes cannot be pursued solely in silico and requires zinc proteomics, an integrated scientific approach. Progress hinges on a combination of bioinformatics, biology, and significantly, analytical and structural chemistry.
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Zaman, Saif, Boris I. Chobrutskiy, Jay S. Patel, Blake M. Callahan, Moody Mihyu, Andrea Diviney, Wei Lue Tong, and George Blanck. "Abstract B12: Potential neoantigen release and increased lymphocyte activity is facilitated by matrix metalloproteinase-dependent cleavage of mutant matrisome peptides in cutaneous melanoma." Cancer Research 80, no. 19_Supplement (October 1, 2020): B12. http://dx.doi.org/10.1158/1538-7445.mel2019-b12.
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Abstract Introduction: Proteases in the cancer microenvironment have been studied for decades, with a general conclusion that such proteases facilitate the spread of cancer, although there is some controversy regrading that conclusion in later stages of cancer development. More recently, a very large collection of data regarding mutant amino acids in the potential substrates of the cancer microenvironment has become available. Methods: To better understand the potential impact of these mutant amino acids on protease function and cancer progression, we established a bioinformatics approach to assessing the impact of melanoma mutants, among a previously defined set of ECM structural proteins, on MMP2, a protease extensively associated with melanoma in terms of both protease sensitivity and MHC class I binding using original software. Additionally, T-cell receptor TRα and TRβ recombinations were bioinformatically obtained using whole-exome sequencing data from 479 melanoma tumor samples. Results: Tumor samples with mutant amino acids adjacent to ECM structural protein, MMP2-cleavage sites represented a better survival rate and a larger proportion of mutant peptides with high HLA class I binding affinities, particularly in comparison to melanoma samples lacking a T-cell infiltrate. Furthermore, even better MHC class I binders, as a group, were identified among the sample representing ECM structural proteins mutants not adjacent to MMP2 sensitive sites and evincing a relatively poor survival rate. Conclusion: Overall, this analysis suggested that MMP2 has the capacity of freeing mutant peptides that could facilitate an antitumor response and a better survival rate, and this analysis has the potential of resolving some of the controversy surrounding the role of cancer proteases in cancer progression. Citation Format: Saif Zaman, Boris I. Chobrutskiy, Jay S. Patel, Blake M. Callahan, Moody Mihyu, Andrea Diviney, Wei Lue Tong, George Blanck. Potential neoantigen release and increased lymphocyte activity is facilitated by matrix metalloproteinase-dependent cleavage of mutant matrisome peptides in cutaneous melanoma [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr B12.
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Prabhakaran, Rajkumar, Sebastin Nirmal Rajkumar, Tharmarajan Ramprasath, and Govindan Sadasivam Selvam. "Identification of promoter PcadR, in silico characterization of cadmium resistant gene cadR and molecular cloning of promoter PcadR from Pseudomonas aeruginosa BC15." Toxicology and Industrial Health 34, no. 12 (November 8, 2018): 819–33. http://dx.doi.org/10.1177/0748233718795934.
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Cadmium (Cd) remediation in Pseudomonas aeruginosa is achieved through the function of two vital genes, cadA and cadR, that code for P-type ATPase (CadA) and transcription regulatory protein (CadR), respectively. Although numerous studies are available on these metal-sensing and regulatory proteins, the promoter of these genes, metal sensing and binding ability, are poorly understood. The present work is aimed at the characterization of the CadR protein, identification of the P cadR promoter and protein–promoter–metal binding affinity using bioinformatics and to validate the results by cloning the P cadR promoter in Escherichia coli DH5α. The promoter regions and its curvature were identified and analysed using PePPER software (University of Groningen, The Netherland) and the Bendit program (Version: v.1.0), respectively. Using Phyre, the three-dimensional structure of CadR was modelled, and the structure was validated by Ramachandran plots. The DNA-binding domain was present in the N-terminal region of CadR. A dimeric interface was observed in helix-turn-helix and metal ion-binding sites at the C-terminal. Docking studies showed higher affinity of Cd to both CadR (Atomic contact energy = −15.04 kcal/Mol) and P cadR (Atomic contact energy = −40.18 kcal/Mol) when compared to other metal ions. CadR with P cadR showed the highest binding affinity (Atomic contact energy= −250.40 kcal/Mol) when compared with P cadA. In vitro studies using green fluorescent protein tagged with P cadR ( gfp-P cadR) cloned in E. coli-expressed gfp protein in a concentration-dependent manner upon Cd exposure. Based on our in silico studies and in vitro molecular cloning analysis, we conclude that P cadR and CadR are active only in the presence of Cd. The CadR protein has the highest binding affinity with P cadR. As it became apparent that the cadR gene regulates the P cadR activity in the presence of Cd with high specificity, and the cadR and P cadR can be used as a biological tool for development of a microbial biosensor.
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Taherkhani, Amir, Zahra Khamverdi, Mahdi Sayafi, and Shirin Moradkhani. "Investigation on Chemical Constituents of Foeniculum vulgare Essential Oil and the Molecular Docking Studies of its Components for Possible Matrix Metalloproteinase-13 Inhibition." Avicenna Journal of Pharmaceutical Research 1, no. 2 (December 30, 2020): 65–71. http://dx.doi.org/10.34172/ajpr.2020.12.
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Background: Foeniculum vulgare (Fennel) has a wide range of applications. Previous studies revealed the presence of different compounds in the essential oil (EO) of fennel fruit (FF). Matrix metalloproteinase-13 (MMP-13) participates in several human biological processes including the degradation of extracellular matrix proteins, activation or degradation of some significant regulatory proteins, and tumor cell invasion. Furthermore, the up-regulation of MMP-13 is associated with many disorders such as tooth caries and periodontitis, as well as the degradation of enamel and tissues around the implant and Alzheimer’s disease. Therefore, the aims of the present study were to investigate the compounds of the EO of FF (EOFF) from the Hamedan district, along with performing molecular docking analysis to assess the binding affinity of four compounds originated from F. vulgare with the MMP-13. Finally, the study focused on evaluating the pharmacokinetic and toxicity characteristics of the compounds. Methods: Hydrodistillation method was used for obtaining the EO from FF. Then, gas chromatography-mass spectrometry was applied to identify the components of the EO. Molecular docking analysis was carried out using AutoDock software. Eventually, the pharmacokinetic and toxicity features of compounds were evaluated using bioinformatics webservers. Results: The results revealed the presence of fourteen compounds, among which e-anethole (86.86%), fenchone (743%), estragole (165%), and thymol (1.21%) were the main components. Based on the results, thymol, fenchone, e-anethole, and estragole could potentially bind to the MMP-13 active site, respectively. Conclusion: Regardless of several studies on the chemical constituents of EOFF, the subject has its own pharmacognostical importance. According to computational studies, EOFF has the potential for study on several human disorders such as cancer, tooth decay, and Alzheimer’s disease.
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Fontes, Marcos, Carlos Fernandes, Juliana dos Santos, Guilherme Salvador, Rafael Borges, Angelo Magro, Fabio Cardoso, and Thiago Dreyer. "Structural basis for a novel model for myotoxic activity on phospholipases A2." Acta Crystallographica Section A Foundations and Advances 70, a1 (August 5, 2014): C114. http://dx.doi.org/10.1107/s2053273314098854.
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Envenoming due to snakebites is an important public health problem in many tropical and subtropical countries which, in addition to mortality, may result in permanent sequelae as a consequence of local tissue damage, i.e. necrosis and hemorrhage. Toxins that play a leading role in the complex pathogenesis of these feared venom actions have been identified as members of the phospholipase A2 (PLA2) and metalloproteinase protein families. Phospholipases A2 are enzymes responsible for cellular membrane disruption through Ca2+-dependent hydrolysis of phospholipids. A class of these proteins (Lys49-PLA2s) does not show catalytic activity but can exert a pronounced local myotoxic effect that is not neutralized by serum therapy. After more than 20 years of structural, biochemical and biological studies with this class of proteins, its biological mechanism still remain not totally understood. Here, based in a comprehensive study including over than 30 crystallographic structures, Small Angle X-ray Scattering, Dynamic Light Scattering, Isothermal Titration Calorimetry, Biochemical, Bioinformatics, Phylogenic and Myografic experiments, we proposed a complete myotoxic mechanism. This work confirms the biological dimer indicated by recent studies in which both C-termini are in the dimeric interface. In this configuration, we propose that the myotoxic site of these toxins is composed by the Lys 20, Lys115 and Arg118 residues. The extensive structural analysis also include: (i) the function of hydrophobic long-chain molecules as Lys49-PLA2s inhibitors, (ii) the role of Lys122, previously indicated as being responsible for Lys49-PLA2s catalytic inactivity, (iii) a structural comparison of the Ca2+-binding loop region between Lys49 and Asp49-PLA2s, (iv) the importance of Tyr119 residue, (v) the role of different classes of inhibitors and (vi) the role of hydrophobic knuckle. Taking into account all these issues we were able to propose a complete mechanism of action of these proteins and also proposed the different ways to inhibit them. These results may be useful to guide new experiments that can definitively clarify the action mechanism of snake venom PLA2s and lead to the design of structure-based inhibitors to complement the serum therapy.
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Akers, Johnny C., HoangMinh HoDac, Richard H. Lathrop, and Ming Tan. "Identification and Functional Analysis of CT069 as a Novel Transcriptional Regulator in Chlamydia." Journal of Bacteriology 193, no. 22 (September 9, 2011): 6123–31. http://dx.doi.org/10.1128/jb.05976-11.
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Only a small number of transcription factors have been predicted inChlamydiaspp., which are obligate intracellular bacteria that include a number of important human pathogens. We used a bioinformatics strategy to identify novel transcriptional regulators from theChlamydia trachomatisgenome by predicting proteins with the general structure and characteristic functional domains of a bacterial transcription factor. With this approach, we identified CT069 as a candidate transcription factor with sequence similarity at its C terminus toTreponema pallidumTroR. Like TroR, the gene for CT069 belongs to an operon that encodes components of a putative ABC transporter for importing divalent metal cations. However, CT069 has been annotated as YtgC because of sequence similarity at its N terminus to TroC, a transmembrane component of this metal ion transporter. Instead, CT069 appears to be a fusion protein composed of YtgC and a TroR ortholog that we have called YtgR. Although it has not been previously reported, a similar YtgC-YtgR fusion protein is predicted to be encoded by otherChlamydiaspp. and several other bacteria, includingBacillus subtilis. We show that recombinant YtgR polypeptide bound specifically to an operator sequence upstream of theytgoperon and that binding was enhanced by Zn2+. We also demonstrate that YtgR repressed transcription from theytgpromoter in a heterologousin vivoreporter assay. These results provide evidence that CT069 is a negative regulator of theytgoperon, which encodes a putative metal ion transporter inC. trachomatis.
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Fonseca-García, Citlali, Claudia Marina López-García, Ronal Pacheco, Elisabeth Armada, Noreide Nava, Rocío Pérez-Aguilar, Jorge Solis-Miranda, and Carmen Quinto. "Metallothionein1A Regulates Rhizobial Infection and Nodulation in Phaseolus vulgaris." International Journal of Molecular Sciences 23, no. 3 (January 27, 2022): 1491. http://dx.doi.org/10.3390/ijms23031491.
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Metallothioneins (MTs) constitute a heterogeneous family of ubiquitous metal ion-binding proteins. In plants, MTs participate in the regulation of cell growth and proliferation, protection against heavy metal stress, oxidative stress responses, and responses to pathogen attack. Despite their wide variety of functions, the role of MTs in symbiotic associations, specifically nodule-fabacean symbiosis, is poorly understood. Here, we analyzed the role of the PvMT1A gene in Phaseolus vulgaris-Rhizobium tropici symbiosis using bioinformatics and reverse genetics approaches. Using in silico analysis, we identified six genes encoding MTs in P. vulgaris, which were clustered into three of the four classes described in plants. PvMT1A transcript levels were significantly higher in roots inoculated with R. tropici at 7 and 30 days post inoculation (dpi) than in non-inoculated roots. Functional analysis showed that downregulating PvMT1A by RNA interference (RNAi) reduced the number of infection events at 7 and 10 dpi and the number of nodules at 14 and 21 dpi. In addition, nodule development was negatively affected in PvMT1A:RNAi transgenic roots, and these nodules displayed a reduced nitrogen fixation rate at 21 dpi. These results strongly suggest that PvMT1A plays an important role in the infection process and nodule development in P. vulgaris during rhizobial symbiosis.
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Neuman, Benjamin W., Jeremiah S. Joseph, Kumar S. Saikatendu, Pedro Serrano, Amarnath Chatterjee, Margaret A. Johnson, Lujian Liao, et al. "Proteomics Analysis Unravels the Functional Repertoire of Coronavirus Nonstructural Protein 3." Journal of Virology 82, no. 11 (March 26, 2008): 5279–94. http://dx.doi.org/10.1128/jvi.02631-07.
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ABSTRACT Severe acute respiratory syndrome (SARS) coronavirus infection and growth are dependent on initiating signaling and enzyme actions upon viral entry into the host cell. Proteins packaged during virus assembly may subsequently form the first line of attack and host manipulation upon infection. A complete characterization of virion components is therefore important to understanding the dynamics of early stages of infection. Mass spectrometry and kinase profiling techniques identified nearly 200 incorporated host and viral proteins. We used published interaction data to identify hubs of connectivity with potential significance for virion formation. Surprisingly, the hub with the most potential connections was not the viral M protein but the nonstructural protein 3 (nsp3), which is one of the novel virion components identified by mass spectrometry. Based on new experimental data and a bioinformatics analysis across the Coronaviridae, we propose a higher-resolution functional domain architecture for nsp3 that determines the interaction capacity of this protein. Using recombinant protein domains expressed in Escherichia coli, we identified two additional RNA-binding domains of nsp3. One of these domains is located within the previously described SARS-unique domain, and there is a nucleic acid chaperone-like domain located immediately downstream of the papain-like proteinase domain. We also identified a novel cysteine-coordinated metal ion-binding domain. Analyses of interdomain interactions and provisional functional annotation of the remaining, so-far-uncharacterized domains are presented. Overall, the ensemble of data surveyed here paint a more complete picture of nsp3 as a conserved component of the viral protein processing machinery, which is intimately associated with viral RNA in its role as a virion component.
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Agrelli, Almerinda, Niedja Fittipaldi Vasconcelos, Rayane Cristine Santos da Silva, Carina Lucena Mendes-Marques, Isabel Renata de Souza Arruda, Priscilla Stela Santana de Oliveira, Luzia Rejane Lisbôa Santos, et al. "Peptides for Coating TiO2 Implants: An In Silico Approach." International Journal of Molecular Sciences 23, no. 22 (November 14, 2022): 14048. http://dx.doi.org/10.3390/ijms232214048.
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Titanium is usually used in the manufacturing of metal implants due to its biocompatibility and high resistance to corrosion. A structural and functional connection between the living bone and the surface of the implant, a process called osseointegration, is mandatory for avoiding prolonged healing, infections, and tissue loss. Therefore, osseointegration is crucial for the success of the implantation procedure. Osseointegration is a process mediated by bone-matrix progenitor cells’ proteins, named integrins. In this study, we used an in silico approach to assemble and test peptides that can be strategically used in sensitizing TiO2 implants in order to improve osseointegration. To do so, we downloaded PDB structures of integrins α5β1, αvβ3, and αIIbβ3; their biological ligands; and low-cost proteins from the Protein Data Bank, and then we performed a primary (integrin-protein) docking analysis. Furthermore, we modeled complex peptides with the potential to bind to the TiO2 surface on the implant, as well as integrins in the bone-matrix progenitor cells. Then we performed a secondary (integrin–peptide) docking analysis. The ten most promising integrin–peptide docking results were further verified by molecular dynamics (MD) simulations. We recognized 82 peptides with great potential to bind the integrins, and therefore to be used in coating TiO2 implants. Among them, peptides 1 (GHTHYHAVRTQTTGR), 3 (RKLPDATGR), and 8 (GHTHYHAVRTQTLKA) showed the highest binding stability during the MD simulations. This bioinformatics approach saves time and more effectively directs in vitro studies.
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Huang, Ke, Yaotang Deng, Wenya Yuan, Jian Geng, Guanghai Wang, and Fei Zou. "Phospholipase D1 Ameliorates Apoptosis in Chronic Renal Toxicity Caused by Low-Dose Cadmium Exposure." BioMed Research International 2020 (March 31, 2020): 1–12. http://dx.doi.org/10.1155/2020/7091053.
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Exposure to cadmium (Cd), a common heavy metal used in industry, can result in long-term chronic toxicity. It has been well characterized that kidneys are the main organs that are targeted by toxicity, which can cause apoptosis, necrosis, and atrophy of renal tubular epithelial cells. However, the molecular mechanisms associated with Cd toxicity remain unclear. In this study, the expression of renal proteins in Sprague-Dawley rats exposed to chronic Cd was analyzed with iTRAQ proteomics. Bioinformatics analysis indicated that phospholipase D1 (PLD1) was significantly underexpressed and may correlate strongly with Cd-induced chronic kidney impairment. Previous studies have shown that PLD1 promotes cell proliferation and inhibits apoptosis, indicating that PLD1 may be implicated in the pathogenesis of kidney injury induced by Cd. Studies in vivo and in vitro all demonstrate that the mRNA and protein levels of PLD1 decrease significantly both in kidney tissue and in proximal tubular cell lines exposed to Cd. Overexpression of PLD1 and its downstream product PA could ameliorate Cd-induced apoptosis. Moreover, we identified that miR-122-5p was a regulatory miRNA of PLD1. miR-122-5p was overexpressed after Cd exposure and promoted cell apoptosis by downregulating PLD1 through binding the 3′UTR of the locus at 1761–1784 nt. In conclusion, our results indicated that PLD1 and its downstream PA were strongly implicated in Cd-induced chronic kidney impairment and could be a novel player in the defense against Cd-induced nephrotoxicity.
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Philpott, Caroline C., Avery G. Frey, Moon-Suhn Ryu, Daniel Palenchar, Justin Wildemann, Ajay A. Vashisht, James Wohlschlegel, and Kymberly Bullough. "Special Delivery: The Role of Iron Chaperones in the Distribution of Iron in Developing Red Cells." Blood 126, no. 23 (December 3, 2015): SCI—45—SCI—45. http://dx.doi.org/10.1182/blood.v126.23.sci-45.sci-45.
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Abstract Iron is an essential nutrient for every cell in the human body, yet it can also be a potent cellular toxin. Iron is essential because enzymes that require iron co-factors (namely, heme, iron-sulfur clusters, mononuclear and diiron centers) are involved in virtually every major metabolic process in the cell. Hundreds of iron, zinc, copper, and manganese proteins are expressed in human cells, yet little is known about the mechanisms by which these metalloproteins acquire their native metal ligands and avoid mis-metallation. Significant advances have been made in understanding the delivery of iron to iron-dependent enzymes in the cytosol. Poly(rC)-binding proteins (PCBPs) are multifunctional adaptors that mediate interactions between single-stranded nucleic acids, iron cofactors, and other proteins, affecting the fate and activity of the components of these interactions. PCBP1 is an iron-binding protein that delivers iron to ferritin in human cells via a direct protein-protein interaction and can be described as an iron chaperone. PCBP2, a human paralog of PCBP1, is also involved in the delivery of iron to ferritin, both in yeast cells and in human cells, suggesting that PCBP1 and PCBP2 work together in iron delivery. PCBP1 and PCBP2 can also deliver iron to the two major families of non-heme iron enzymes: the mononuclear and dinuclear iron-dependent oxygenases. The prolyl hydroxylases (PHDs) are mononuclear iron enzymes that regulate the degradation of hypoxia inducible factor 1 (HIF1). Misregulation of the HIF transcription factors leads to the development of a variety of cancers in humans. Cells depend on the iron chaperones PCBP1 and PCBP2 to maintain iron in the enzymatic active site of PHDs and the related enzyme, asparagyl hydroxylase and to maintain proper regulation of HIF1a, especially under conditions of iron limitation. Deoxyhypusine hydroxylase (DOHH) is a dinuclear iron enzyme that is required for the posttranslational modification of a single lysine residue on eukaryotic initiation factor 5A (eIF5A). EIF5A and the conversion of this conserved lysine to hypusine are essential in all eukaryotes, as it enables the translation of peptides containing polyproline sequences. We found that cells depleted of PCBP1 or PCBP2 exhibited reduced activity of DOHH, which was due to a loss of iron in the active site of the enzyme. Thus, PCBPs are basic components of a cytosolic iron delivery system that serves both of the major classes of non-heme iron enzymes in the cytosol. Recent work has indicated that a second type of iron delivery system in the cytosol is mediated by a monothiol glutaredoxin, Glrx3, which, in vitro, can bind and transfer iron-sulfur clusters to recipient apo-iron-sulfur proteins. We have determined that PCBP1 directly interacts with Glrx3-containing complexes and can affect the coordination of iron-sulfur clusters by Glrx3. The huge flux of iron through the developing erythroid cell represents unique challenges for the utilization of cellular iron. We have examined the role of PCBPs as iron chaperones in terminal erythroid differentiation. The role of ferritin in erythroid cell maturation is controversial, but our data indicate that ferritin, PCBPs and NCOA4 are critical factors in erythrocyte development. The flux of iron through ferritin via the lysosome appears to be critical for the transfer of iron to mitochondria for heme synthesis. Disclosures No relevant conflicts of interest to declare.
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Akcapinar, Gunseli Bayram, and Osman Ugur Sezerman. "Computational approaches for de novo design and redesign of metal-binding sites on proteins." Bioscience Reports 37, no. 2 (March 27, 2017). http://dx.doi.org/10.1042/bsr20160179.
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Metal ions play pivotal roles in protein structure, function and stability. The functional and structural diversity of proteins in nature expanded with the incorporation of metal ions or clusters in proteins. Approximately one-third of these proteins in the databases contain metal ions. Many biological and chemical processes in nature involve metal ion-binding proteins, aka metalloproteins. Many cellular reactions that underpin life require metalloproteins. Most of the remarkable, complex chemical transformations are catalysed by metalloenzymes. Realization of the importance of metal-binding sites in a variety of cellular events led to the advancement of various computational methods for their prediction and characterization. Furthermore, as structural and functional knowledgebase about metalloproteins is expanding with advances in computational and experimental fields, the focus of the research is now shifting towards de novo design and redesign of metalloproteins to extend nature’s own diversity beyond its limits. In this review, we will focus on the computational toolbox for prediction of metal ion-binding sites, de novo metalloprotein design and redesign. We will also give examples of tailor-made artificial metalloproteins designed with the computational toolbox.
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Aptekmann, A. A., J. Buongiorno, D. Giovannelli, M. Glamoclija, D. U. Ferreiro, and Y. Bromberg. "mebipred: identifying metal binding potential in protein sequence." Bioinformatics, May 27, 2022. http://dx.doi.org/10.1093/bioinformatics/btac358.
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Abstract Motivation Metal binding proteins have a central role in maintaining life processes. Nearly one-third of known protein structures contain metal ions that are used for a variety of needs, such as catalysis, DNA/RNA binding, protein structure stability, etc. Identifying metal binding proteins is thus crucial for understanding the mechanisms of cellular activity. However, experimental annotation of protein metal binding potential is severely lacking, while computational techniques are often imprecise and of limited applicability. Results We developed a novel machine learning-based method, mebipred, for identifying metal binding proteins from sequence-derived features. This method is over 80% accurate in recognizing proteins that bind metal ion-containing ligands; the specific identity of eleven ubiquitously-present metal ions can also be annotated. mebipred is reference-free, i.e. no sequence alignments are involved, and is thus faster than alignment-based methods; it also more accurate than other sequence-based prediction methods. Additionally, mebipred can identify protein metal binding capabilities from short sequence stretches, e.g. translated sequencing reads, and, thus, may be useful for the annotation of metal requirements of metagenomic samples. We performed an analysis of available microbiome data and found that ocean, hot spring sediments, and soil microbiomes use a more diverse set of metals than human host-related ones. For human microbiomes, physiological conditions explain the observed metal preferences. Similarly, subtle changes in ocean sample ion concentration affect the abundance of relevant metal binding proteins. These results highlight mebipred’s utility in analysing microbiome metal requirements. Availability mebipred is available as a web server at services.bromberglab.org/mebipred and as a standalone package at https://pypi.org/project/mymetal/. Supplementary information Supplementary data are available from Bioinformatics online repository. Additional data is available from http://dx.doi.org/10.5281/zenodo.5722730 and http://dx.doi.org/10.5281/zenodo.6332940.
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Klein, Andreas S., and Cathleen Zeymer. "Design and engineering of artificial metalloproteins: from de novo metal coordination to catalysis." Protein Engineering, Design and Selection 34 (2021). http://dx.doi.org/10.1093/protein/gzab003.
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Abstract Metalloproteins are essential to sustain life. Natural evolution optimized them for intricate structural, regulatory and catalytic functions that cannot be fulfilled by either a protein or a metal ion alone. In order to understand this synergy and the complex design principles behind the natural systems, simpler mimics were engineered from the bottom up by installing de novo metal sites in either natural or fully designed, artificial protein scaffolds. This review focuses on key challenges associated with this approach. We discuss how proteins can be equipped with binding sites that provide an optimal coordination environment for a metal cofactor of choice, which can be a single metal ion or a complex multinuclear cluster. Furthermore, we highlight recent studies in which artificial metalloproteins were engineered towards new functions, including electron transfer and catalysis. In this context, the powerful combination of de novo protein design and directed evolution is emphasized for metalloenzyme development.
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Lu, Chih-Hao, Chih-Chieh Chen, Chin-Sheng Yu, Yen-Yi Liu, Jia-Jun Liu, Sung-Tai Wei, and Yu-Feng Lin. "MIB2: Metal ion-binding site prediction and modeling server." Bioinformatics, July 29, 2022. http://dx.doi.org/10.1093/bioinformatics/btac534.
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Abstract Motivation MIB2 attempts to overcome the limitation of structure-based prediction approaches, with many proteins lacking a solved structure. MIB2 also offers more accurate prediction performance and more metal ion types. Results MIB2 utilizes both the (PS)2 method and the AlphaFold Protein Structure Database to acquire predicted structures to perform metal ion docking and predict binding residues. MIB2 offers marked improvements over MIB by collecting more metal ion-binding residue templates and using the metal ion type-specific scoring function. It offers a total of 18 types of metal ions for binding site predictions. Availability Freely available on the web at http://bioinfo.cmu.edu.tw/MIB2/. Supplementary information Supplementary data are available at Bioinformatics online.
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Anirudhan, Athira, Paola Isabel Angulo-Bejarano, Prabu Paramasivam, Kalaivani Manokaran, S. Manjunath Kamath, Ram Murugesan, Ashutosh Sharma, and Shiek S. S. J. Ahmed. "RPL6: A Key Molecule Regulating Zinc- and Magnesium-Bound Metalloproteins of Parkinson’s Disease." Frontiers in Neuroscience 15 (March 11, 2021). http://dx.doi.org/10.3389/fnins.2021.631892.
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Parkinson’s disease (PD) is a progressive neurodegenerative disease with no definite molecular markers for diagnosis. Metal exposure may alter cellular proteins that contribute to PD. Exploring the cross-talk between metal and its binding proteins in PD could reveal a new strategy for PD diagnosis. We performed a meta-analysis from different PD tissue microarray datasets to identify differentially expressed genes (DEGs) common to the blood and brain. Among common DEGs, we extracted 280 metalloprotein-encoding genes to construct protein networks describing the regulation of metalloproteins in the PD blood and brain. From the metalloprotein network, we identified three important functional hubs. Further analysis shows 60S ribosomal protein L6 (RPL6), a novel intermediary molecule connecting the three hubs of the metalloproteins network. Quantitative real-time PCR analysis showed that RPL6 was downregulated in PD peripheral blood mononuclear cell (PBMC) samples. Simultaneously, trace element analysis revealed altered serum zinc and magnesium concentrations in PD samples. The Pearson’s correlation analysis shows that serum zinc and magnesium regulate the RPL6 gene expression in PBMC. Thus, metal-regulating RPL6 acts as an intermediary molecule connecting the three hubs that are functionally associated with PD. Overall our study explores the understanding of metal-mediated pathogenesis in PD, which provides a serum metal environment regulating the cellular gene expression that may light toward metal and gene expression-based biomarkers for PD diagnosis.
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Roumenina, Lubka T., and Jordan D. Dimitrov. "Assessment of the breadth of binding promiscuity of heme towards human proteins." Biological Chemistry, October 18, 2022. http://dx.doi.org/10.1515/hsz-2022-0226.
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Abstract Heme regulates important biological processes by transient interactions with many human proteins. The goal of the present study was to assess extends of protein binding promiscuity of heme. To this end we evaluated interaction of heme with >9000 human proteins. Heme manifested high binding promiscuity by binding to most of the proteins in the array. Nevertheless, some proteins have outstanding heme binding capacity. Bioinformatics analyses revealed that apart from typical haemoproteins, these proteins are frequently involved in metal binding or have the potential to recognize DNA. This study can contribute for understanding the regulatory functions of labile heme.
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Roy, Parthajit, and Dhananjay Bhattacharyya. "MetBP: A Software Tool for Detection of Interaction between Metal Ion-RNA Base Pairs." Bioinformatics, June 13, 2022. http://dx.doi.org/10.1093/bioinformatics/btac392.
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Abstract Motivation The role of metals in shaping and functioning of RNA is a well established fact and the understanding of that through the analysis of structural data has biological relevance. Often metal ions bind to one or more atoms of the nucleobase of an RNA. This fact becomes more interesting when such bases form a base pair with any other base. Furthermore, when metal ions bind to any residue of an RNA, the secondary structural features of the residue (helix, loop, unpaired etc) are also biologically important. The available metal binding related software tools cannot address such type specific queries. Results To fill this limitation, we have designed a software tool, called MetBP, that meets the goal. This tool is a stand-alone command line based tool and has no dependency on the other existing software. It accepts a structure file in mmCIF or PDB format and computes the base pairs and thereafter reports all metals that bind to one or more nucleotides that form pairs with another. It reports binding distance, angles along with base pair stability. It also reports several other important aspects, e.g. secondary structure of the residue in the RNA. MetBP can be used as a generalized metal binding site detection tool for Proteins and DNA as well. Availability https://github.com/computational-biology/metbp Supplementary information Supplementary data are available at Bioinformatics online.
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Bellotti, Denise, Magdalena Rowińska-Żyrek, and Maurizio Remelli. "How Zinc-binding Systems, Expressed by Human Pathogens, Acquire Zinc from the Colonized Host Environment: A Critical Review on Zincophores." Current Medicinal Chemistry 28 (May 14, 2021). http://dx.doi.org/10.2174/1389200222666210514012945.
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Some transition metals, like manganese, iron, cobalt, nickel, copper and zinc, required for the biosynthesis of metalloenzymes and metalloproteins, are essential micronutrients for the growth and development of pathogenic microorganisms. Among the defenses put in place by the host organism, the so-called "nutritional immunity" consists of reducing the availability of micronutrients and thus "starving" the pathogen. In the case of metals, microorganisms can fight the nutritional immunity in different ways, i.e. by directly recruiting the metal ion or capturing an extracellular metalloprotein or also through the synthesis of specific metallophores which allow importing metal in the form of a chelate complex. The best known and most studied metallophores are those directed to iron (siderophores), but analogous chelators are also expressed by microorganisms to capture other metals, such as zinc. Efficient zinc recruitment can also be achieved by means of specialized zinc-binding proteins. Deep knowledge of the properties, structure and action mechanisms of extracytoplasmic zinc chelators can be a powerful tool to find out new therapeutic strategies against antibiotic and/or antifungal resistance. This review aims to collect the knowledge concerning zincophores (small molecules and proteins in charge of zinc acquisition) expressed by bacterial or fungal microorganisms that are pathogenic for the human body.
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Taherkhani, Amir, Shirin Moradkhani, Athena Orangi, Alireza Jalalvand, and Zahra Khamverdi. "Molecular docking study of flavonoid compounds for possible matrix metalloproteinase-13 inhibition." Journal of Basic and Clinical Physiology and Pharmacology, December 11, 2020. http://dx.doi.org/10.1515/jbcpp-2020-0036.
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AbstractObjectivesMatrix metalloproteinase-13 (MMP-13) has been reported to be involved in different biological processes such as degradation of extracellular matrix proteins, activating or degrading some significant regulatory proteins, wound healing, tissue remodeling, cartilage degradation, bone development, bone mineralization, ossification, cell migration, and tumor cell invasion. Further, MMP-13 participates in many oral diseases such as tooth decay, gingivitis, and degradation of enamel and tissue around the implant. In addition, inhibition of MMP-13 has shown therapeutic properties for Alzheimer’s disease (AD). We performed molecular docking to assess the binding affinity of 29 flavonoid compounds with the MMP-13. Additionally, pharmacokinetic and toxicity characteristics of the top-ranked flavonoids were studied. The current study also intended to identify the most important amino acids involved in the inhibition of MMP-13 based on topological feature (degree) in the ligand-amino acid network for MMP-13.MethodsMolecular docking and network analysis were studied using AutoDock and Cytoscape software, respectively. Pharmacokinetic and toxicity characteristics of compounds were predicted using bioinformatics web tools.ResultsThe results revealed that nine of the studied flavonoids had considerable estimated free energy of binding and inhibition constant: Rutin, nicotiflorin, orientin, vitexin, apigenin-7-glucoside, quercitrin, isoquercitrin, quercitrin-3-rhamnoside, and vicenin-2. Proline-242 was found to be the most important amino acid inhibiting the enzyme.ConclusionsThe results of the current study may be helpful in the prevention and therapeutic procedures of many disorders such as cancer, tooth caries, and AD. Nevertheless, validation tests are required in the future.
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Hirakawa, Yoshihisa, Miki Senda, Kodai Fukuda, Hong Yang Yu, Masaki Ishida, Masafumi Taira, Kazushi Kinbara, and Toshiya Senda. "Characterization of a novel type of carbonic anhydrase that acts without metal cofactors." BMC Biology 19, no. 1 (May 18, 2021). http://dx.doi.org/10.1186/s12915-021-01039-8.
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Abstract Background Carbonic anhydrases (CAs) are universal metalloenzymes that catalyze the reversible conversion of carbon dioxide (CO2) and bicarbonate (HCO3-). They are involved in various biological processes, including pH control, respiration, and photosynthesis. To date, eight evolutionarily unrelated classes of CA families (α, β, γ, δ, ζ, η, θ, and ι) have been identified. All are characterized by an active site accommodating the binding of a metal cofactor, which is assumed to play a central role in catalysis. This feature is thought to be the result of convergent evolution. Results Here, we report that a previously uncharacterized protein group, named “COG4337,” constitutes metal-independent CAs from the newly discovered ι-class. Genes coding for COG4337 proteins are found in various bacteria and photosynthetic eukaryotic algae. Biochemical assays demonstrated that recombinant COG4337 proteins from a cyanobacterium (Anabaena sp. PCC7120) and a chlorarachniophyte alga (Bigelowiella natans) accelerated CO2 hydration. Unexpectedly, these proteins exhibited their activity under metal-free conditions. Based on X-ray crystallography and point mutation analysis, we identified a metal-free active site within the cone-shaped α+β barrel structure. Furthermore, subcellular localization experiments revealed that COG4337 proteins are targeted into plastids and mitochondria of B. natans, implicating their involvement in CO2 metabolism in these organelles. Conclusions COG4337 proteins shared a short sequence motif and overall structure with ι-class CAs, whereas they were characterized by metal independence, unlike any known CAs. Therefore, COG4337 proteins could be treated as a variant type of ι-class CAs. Our findings suggested that this novel type of ι-CAs can function even in metal-poor environments (e.g., the open ocean) without competition with other metalloproteins for trace metals. Considering the widespread prevalence of ι-CAs across microalgae, this class of CAs may play a role in the global carbon cycle.