Journal articles: 'Protein; Ligands'

1

Karasev, Dmitry, Boris Sobolev, Alexey Lagunin, Dmitry Filimonov, and Vladimir Poroikov. "Prediction of Protein–ligand Interaction Based on Sequence Similarity and Ligand Structural Features." International Journal of Molecular Sciences 21, no. 21 (October 31, 2020): 8152. http://dx.doi.org/10.3390/ijms21218152.

Full text

Abstract:

Computationally predicting the interaction of proteins and ligands presents three main directions: the search of new target proteins for ligands, the search of new ligands for targets, and predicting the interaction of new proteins and new ligands. We proposed an approach providing the fuzzy classification of protein sequences based on the ligand structural features to analyze the latter most complicated case. We tested our approach on five protein groups, which represented promised targets for drug-like ligands and differed in functional peculiarities. The training sets were built with the original procedure overcoming the data ambiguity. Our study showed the effective prediction of new targets for ligands with an average accuracy of 0.96. The prediction of new ligands for targets displayed the average accuracy 0.95; accuracy estimates were close to our previous results, comparable in accuracy to those of other methods or exceeded them. Using the fuzzy coefficients reflecting the target-to-ligand specificity, we provided predicting interactions for new proteins and new ligands; the obtained accuracy values from 0.89 to 0.99 were acceptable for such a sophisticated task. The protein kinase family case demonstrated the ability to account for subtle features of proteins and ligands required for the specificity of protein–ligand interaction.

APA, Harvard, Vancouver, ISO, and other styles

2

Southern, Craig, Jennifer M. Cook, Zaynab Neetoo-Isseljee, Debra L. Taylor, Catherine A. Kettleborough, Andy Merritt, Daniel L. Bassoni, et al. "Screening β-Arrestin Recruitment for the Identification of Natural Ligands for Orphan G-Protein–Coupled Receptors." Journal of Biomolecular Screening 18, no. 5 (February 8, 2013): 599–609. http://dx.doi.org/10.1177/1087057113475480.

Full text

Abstract:

A variety of G-protein–coupled receptor (GPCR) screening technologies have successfully partnered a number of GPCRs with their cognate ligands. GPCR-mediated β-arrestin recruitment is now recognized as a distinct intracellular signaling pathway, and ligand-receptor interactions may show a bias toward β-arrestin over classical GPCR signaling pathways. We hypothesized that the failure to identify native ligands for the remaining orphan GPCRs may be a consequence of biased β-arrestin signaling. To investigate this, we assembled 10 500 candidate ligands and screened 82 GPCRs using PathHunter β-arrestin recruitment technology. High-quality screening assays were validated by the inclusion of liganded receptors and the detection and confirmation of these established ligand-receptor pairings. We describe a candidate endogenous orphan GPCR ligand and a number of novel surrogate ligands. However, for the majority of orphan receptors studied, measurement of β-arrestin recruitment did not lead to the identification of cognate ligands from our screening sets. β-Arrestin recruitment represents a robust GPCR screening technology, and ligand-biased signaling is emerging as a therapeutically exploitable feature of GPCR biology. The identification of cognate ligands for the orphan GPCRs and the extent to which receptors may exist to preferentially signal through β-arrestin in response to their native ligand remain to be determined.

APA, Harvard, Vancouver, ISO, and other styles

3

Finkina, Ekaterina I., Daria N. Melnikova, Ivan V. Bogdanov, Natalia S. Matveevskaya, Anastasia A. Ignatova, Ilia Y. Toropygin, and Tatiana V. Ovchinnikova. "Impact of Different Lipid Ligands on the Stability and IgE-Binding Capacity of the Lentil Allergen Len c 3." Biomolecules 10, no. 12 (December 13, 2020): 1668. http://dx.doi.org/10.3390/biom10121668.

Full text

Abstract:

Previously, we isolated the lentil allergen Len c 3, belonging to the class of lipid transfer proteins, cross-reacting with the major peach allergen Pru p 3 and binding lipid ligands. In this work, the allergenic capacity of Len c 3 and effects of different lipid ligands on the protein stability and IgE-binding capacity were investigated. Impacts of pH and heat treating on ligand binding with Len c 3 were also studied. It was shown that the recombinant Len c 3 (rLen c 3) IgE-binding capacity is sensitive to heating and simulating of gastroduodenal digestion. While being heated or digested, the protein showed a considerably lower capacity to bind specific IgE in sera of allergic patients. The presence of lipid ligands increased the thermostability and resistance of rLen c 3 to digestion, but the level of these effects was dependent upon the ligand’s nature. The anionic lysolipid LPPG showed the most pronounced protective effect which correlated well with experimental data on ligand binding. Thus, the Len c 3 stability and allergenic capacity can be retained in the conditions of food heat cooking and gastroduodenal digestion due to the presence of certain lipid ligands.

APA, Harvard, Vancouver, ISO, and other styles

4

Raingeval, Claire, and Isabelle Krimm. "NMR investigation of protein–ligand interactions for G-protein coupled receptors." Future Medicinal Chemistry 11, no. 14 (July 2019): 1811–25. http://dx.doi.org/10.4155/fmc-2018-0312.

Full text

Abstract:

In this review, we report NMR studies of ligand–GPCR interactions, including both ligand-observed and protein-observed NMR experiments. Published studies exemplify how NMR can be used as a powerful tool to design novel GPCR ligands and investigate the ligand-induced conformational changes of GPCRs. The strength of NMR also lies in its capability to explore the diverse signaling pathways and probe the allosteric modulation of these highly dynamic receptors. By offering unique opportunities for the identification, structural and functional characterization of GPCR ligands, NMR will likely play a major role for the generation of novel molecules both as new tools for the understanding of the GPCR function and as therapeutic compounds for a large diversity of pathologies.

APA, Harvard, Vancouver, ISO, and other styles

5

Hutchens, T. W., and J. O. Porath. "Protein recognition of immobilized ligands: promotion of selective adsorption." Clinical Chemistry 33, no. 9 (September 1, 1987): 1502–8. http://dx.doi.org/10.1093/clinchem/33.9.1502.

Full text

Abstract:

Abstract We are using simple immobilized ligands to evaluate the biochemistry and mechanisms of selective, high-affinity, protein adsorption events. Several specific means have recently been developed to more selectively utilize the favorable entropy changes associated with the displacement of protein-bound water during the formation and stabilization of protein-ligand recognition events. For protein and peptide immobilization these include, besides hydrophobic interaction, for example, metal ion, pi-electron-mediated, and thiophilic interactions. This latter type of protein-ligand recognition process represents a previously unrecognized interaction mechanism of considerable selectivity, affinity, and utility. Specific examples of the above-mentioned principles and protein fractionations include (a) thiophilic adsorption of immunoglobulins to achieve immunoglobulin-free serum for in vitro production and purification of monoclonal antibodies and (b) urea-induced binding of estrogen-receptor proteins to immobilized DNA. The interaction mechanisms are discussed in terms of the molecular architecture of protein surfaces. We present possibilities for the further utilization of these immobilized ligands and their associated proteins in the areas of clinical biochemistry and immunology.

APA, Harvard, Vancouver, ISO, and other styles

6

Mary, Sophie, Jean-Alain Fehrentz, Marjorie Damian, Pascal Verdié, Jean Martinez, Jacky Marie, and Jean-Louis Banères. "How ligands and signalling proteins affect G-protein-coupled receptors' conformational landscape." Biochemical Society Transactions 41, no. 1 (January 29, 2013): 144–47. http://dx.doi.org/10.1042/bst20120267.

Full text

Abstract:

The dynamic character of GPCRs (G-protein-coupled receptors) is essential to their function. However, the details of how ligands and signalling proteins stabilize a receptor conformation to trigger the activation of a given signalling pathway remain largely unexplored. Multiple data, including recent results obtained with the purified ghrelin receptor, suggest a model where ligand efficacy and functional selectivity are directly related to different receptor conformations. Importantly, distinct effector proteins (G-proteins and arrestins) as well as ligands are likely to affect the conformational landscape of GPCRs in different manners, as we show with the isolated ghrelin receptor. Such modulation of the GPCR conformational landscape by pharmacologically distinct ligands and effector proteins has major implications for the design of new drugs that activate specific signalling pathways.

APA, Harvard, Vancouver, ISO, and other styles

7

Galano-Frutos, Juan J., M. Carmen Morón, and Javier Sancho. "The mechanism of water/ion exchange at a protein surface: a weakly bound chloride in Helicobacter pylori apoflavodoxin." Physical Chemistry Chemical Physics 17, no. 43 (2015): 28635–46. http://dx.doi.org/10.1039/c5cp04504e.

Full text

APA, Harvard, Vancouver, ISO, and other styles

8

Ferreira de Freitas, Renato, and Matthieu Schapira. "A systematic analysis of atomic protein–ligand interactions in the PDB." MedChemComm 8, no. 10 (2017): 1970–81. http://dx.doi.org/10.1039/c7md00381a.

Full text

Abstract:

We compiled a list of 11 016 unique structures of small-molecule ligands bound to proteins representing 750 873 protein–ligand atomic interactions, and analyzed the frequency, geometry and the impact of each interaction type. The most frequent ligand–protein atom pairs can be clustered into seven interaction types.

APA, Harvard, Vancouver, ISO, and other styles

9

Mehta, Simpi, and Seema R. Pathak. "INSILICO DRUG DESIGN AND MOLECULAR DOCKING STUDIES OF NOVEL COUMARIN DERIVATIVES AS ANTI-CANCER AGENTS." Asian Journal of Pharmaceutical and Clinical Research 10, no. 4 (April 1, 2017): 335. http://dx.doi.org/10.22159/ajpcr.2017.v10i4.16826.

Full text

Abstract:

Objective: Cancer is the major worldwide problem. It arises due to uncontrolled growth of cells. In the present study a series of novel coumarin derivatives were designed and computationallyoptimized to investigate the interaction between designed ligands and 10 pdb files of five selected proteins. The objective here was to analyse in silico anticancerous activity of designed ligands to reduce cost and time for getting novel anticancerous drug with minimum side effects.Methods: Docking studies were performed to find outmaximum interaction between designed ligands and selected five proteins using Schrondinger software Maestro. Capecitabin has been used as reference compound. Structures of selected proteins were downloaded from protein data bank.Results: All the designed ligands showed mild to excellent binding with proteins.Most of the ligands exhibited better interaction compared to reference compoundcapacitabin with all pdb files. Some of designed ligands amongst (1-7) showed excellent docking score with all pdb files(2v5z, 2v60, 2v61) ofAmine oxidase. Conclusion: All the designed ligands were docked with ten pdb files of five different proteins and it was found that out of seven designed ligand, ligand 4 showed best binding (docking score -10.139 ) with pdb 2v5z of protein Amine oxidase. Docked ligand cavity of ligand 4 showed important hydrophobic/non polar residues such asIle199,Ile316,Trp119,Phe168,Ile198,Cys172,Tyr188,Tyr398,Tyr435,Phe343,Tyr60,Leu328,Leu171 and showed pi-pi interaction with Tyr326.Further wet lab studies are continued in our laboratory to confirm and find out efficiency and activity of target compounds.Keywords: Docking, Mono Amine Oxidase, Coumarin derivatives, Anticancerous activity, binding energy, Ramachandran Plot, Hydrophobic residue.

APA, Harvard, Vancouver, ISO, and other styles

10

GORETZKI, Lothar, and Barbara M. MUELLER. "Low-density-lipoprotein-receptor-related protein (LRP) interacts with a GTP-binding protein." Biochemical Journal 336, no. 2 (December 1, 1998): 381–86. http://dx.doi.org/10.1042/bj3360381.

Full text

Abstract:

The low-density-lipoprotein-receptor-related protein (LRP) binds and internalizes numerous ligands, including lipoproteins, proteinase–inhibitor complexes and others. We have shown previously that LRP-mediated ligand internalization is dependent on cAMP-dependent protein kinase (PKA) activity. Here, we investigated whether ligation of LRP increases the intracellular cAMP level and PKA activity via a stimulatory GTP-binding protein. Treatment of LRP-expressing cell lines with the LRP ligands lactoferrin or urokinase-type plasminogen activator caused a significant elevation in cAMP and stimulated PKA activity in a dose-dependent manner. Addition of the 39 kDa receptor-associated protein (RAP), an antagonist for ligand interactions with LRP, blocked the lactoferrin-induced increase in PKA activity, demonstrating a requirement for ligand binding to LRP. Incubation of cell membrane fractions with lactoferrin increased GTPase activity in a time- and dose-dependent manner, and treatment with LRP ligands suppressed cholera-toxin-mediated ADP-ribosylation of the Gsα subunit of a heterotrimeric G-protein. Affinity precipitation of LRP with RAP resulted in co-precipitation of two isoforms of Gsα from detergent extracts. We thus conclude that LRP is a signalling receptor that associates directly with a stimulatory heterotrimeric G-protein and activates a downstream PKA-dependent pathway.

APA, Harvard, Vancouver, ISO, and other styles

11

Féau, Clémentine, Leggy A. Arnold, Aaron Kosinski, and R. Kiplin Guy. "A High-Throughput Ligand Competition Binding Assay for the Androgen Receptor and Other Nuclear Receptors." Journal of Biomolecular Screening 14, no. 1 (November 21, 2008): 43–48. http://dx.doi.org/10.1177/1087057108326662.

Full text

Abstract:

Standardized, automated ligand-binding assays facilitate evaluation of endocrine activities of environmental chemicals and identification of antagonists of nuclear receptor ligands. Many current assays rely on fluorescently labeled ligands that are significantly different from the native ligands. The authors describe a radiolabeled ligand competition scintillation proximity assay (SPA) for the androgen receptor (AR) using Ni-coated 384-well FlashPlates® and liganded AR-LBD protein. This highly reproducible, low-cost assay is well suited for automated high-throughput screening. In addition, the authors show that this assay can be adapted to measure ligand affinities for other nuclear receptors (peroxisome proliferation-activated receptor γ, thyroid receptors α and β). ( Journal of Biomolecular Screening 2009:43-48)

APA, Harvard, Vancouver, ISO, and other styles

12

Shoda, Takuji, Nobumichi Ohoka, Genichiro Tsuji, Takuma Fujisato, Hideshi Inoue, Yosuke Demizu, Mikihiko Naito, and Masaaki Kurihara. "Targeted Protein Degradation by Chimeric Compounds using Hydrophobic E3 Ligands and Adamantane Moiety." Pharmaceuticals 13, no. 3 (February 25, 2020): 34. http://dx.doi.org/10.3390/ph13030034.

Full text

Abstract:

Targeted protein degradation using small chimeric molecules, such as proteolysis-targeting chimeras (PROTACs) and specific and nongenetic inhibitors of apoptosis protein [IAP]-dependent protein erasers (SNIPERs), is a promising technology in drug discovery. We recently developed a novel class of chimeric compounds that recruit the aryl hydrocarbon receptor (AhR) E3 ligase complex and induce the AhR-dependent degradation of target proteins. However, these chimeras contain a hydrophobic AhR E3 ligand, and thus, degrade target proteins even in cells that do not express AhR. In this study, we synthesized new compounds in which the AhR ligands were replaced with a hydrophobic adamantane moiety to investigate the mechanisms of AhR-independent degradation. Our results showed that the compounds, 2, 3, and 16 induced significant degradation of some target proteins in cells that do not express AhR, similar to the chimeras containing AhR ligands. However, in cells expressing AhR, 2, 3, and 16 did not induce the degradation of other target proteins, in contrast with their response to chimeras containing AhR ligands. Overall, it was suggested that target proteins susceptible to the hydrophobic tagging system are degraded by chimeras containing hydrophobic AhR ligands even without AhR.

APA, Harvard, Vancouver, ISO, and other styles

13

Chavan, Tanmay, Merritt Maduke, and Kenton Swartz. "Protein ligands for studying ion channel proteins." Journal of General Physiology 149, no. 4 (March 7, 2017): 407–11. http://dx.doi.org/10.1085/jgp.201711776.

Full text

APA, Harvard, Vancouver, ISO, and other styles

14

Karasev, Dmitry, Boris Sobolev, Alexey Lagunin, Dmitry Filimonov, and Vladimir Poroikov. "Prediction of Protein–Ligand Interaction Based on the Positional Similarity Scores Derived from Amino Acid Sequences." International Journal of Molecular Sciences 21, no. 1 (December 18, 2019): 24. http://dx.doi.org/10.3390/ijms21010024.

Full text

Abstract:

The affinity of different drug-like ligands to multiple protein targets reflects general chemical–biological interactions. Computational methods estimating such interactions analyze the available information about the structure of the targets, ligands, or both. Prediction of protein–ligand interactions based on pairwise sequence alignment provides reasonable accuracy if the ligands’ specificity well coincides with the phylogenic taxonomy of the proteins. Methods using multiple alignment require an accurate match of functionally significant residues. Such conditions may not be met in the case of diverged protein families. To overcome these limitations, we propose an approach based on the analysis of local sequence similarity within the set of analyzed proteins. The positional scores, calculated by sequence fragment comparisons, are used as input data for the Bayesian classifier. Our approach provides a prediction accuracy comparable or exceeding those of other methods. It was demonstrated on the popular Gold Standard test sets, presenting different sequence heterogeneity and varying from the group, including different protein families to the more specific groups. A reasonable prediction accuracy was also found for protein kinases, displaying weak relationships between sequence phylogeny and inhibitor specificity. Thus, our method can be applied to the broad area of protein–ligand interactions.

APA, Harvard, Vancouver, ISO, and other styles

15

Kuldeep Patel, Richa Dubey, Shaifali Soni, Jagdish Chandra Rathi, and Neerupma Dhiman. "Molecular Docking and ADME Study of Quinoline and Chalcone based Derivatives for Anti-Cancer Activity." International Journal of Research in Pharmaceutical Sciences 12, no. 3 (September 13, 2021): 2252–64. http://dx.doi.org/10.26452/ijrps.v12i3.4849.

Full text

Abstract:

Cancer is a big issue that affects people all over the world. It develops as a result of uncontrolled cell growth. The interaction between developed ligands and thymine phosphorylation was investigated in this study, which was computationally optimized. The aim of this study was to examine the anticancerous activity of designed ligands in thymine phosphorylation (PDB ID: 1UOU) in order to minimize the cost and time required to develop a novel anticancer drug with minimal side effects. All the designed ligands showed mild to excellent binding with proteins. Most of the ligands exhibited better interaction compared to reference compound Tamoxifen with pdb files. Some of the designed ligands among (1-7) in qunoline derivatives and (1-5) in Chalcone derivatives showed excellent docking scores with PDB file (1UOU) of thymine phosphorylation. All the designed ligands and Zinc databases were docked with 1UOU PDB files of protein, and it was found that out of twenty-five designed ligands in Qunoline series, ligand 25 showed the best binding (docking score −8.268) with 1UOU PDB of protein thymine phosphorylation. And that out of ten designed ligands in Chalcone series, ligand K1 showed the best binding (docking score −9.433) with 1UOU PDB of protein thymine phosphorylation. Docked ligand cavity of ligand ku 25 in qunoline series and K 9 in Chalcone series showed important hydrophobic/non-polar residues such as Ile199, Ile316, Trp119, Phe168, Ile198, Cys172, Tyr188, Tyr398, Tyr435, Phe343, Tyr60, Leu328, Leu171, and showed pi-pi interaction with Tyr326. Further wet laboratory studies are continued in our laboratory to confirm and find out the efficiency and activity of target compounds.

APA, Harvard, Vancouver, ISO, and other styles

16

Stefansson, S., M. Z. Kounnas, J. Henkin, R. K. Mallampalli, D. A. Chappell, D. K. Strickland, and W. S. Argraves. "gp330 on type II pneumocytes mediates endocytosis leading to degradation of pro-urokinase, plasminogen activator inhibitor-1 and urokinase-plasminogen activator inhibitor-1 complex." Journal of Cell Science 108, no. 6 (June 1, 1995): 2361–68. http://dx.doi.org/10.1242/jcs.108.6.2361.

Full text

Abstract:

Glycoprotein 330 (gp330) is a member of a family of receptors related to the low density lipoprotein receptor (LDLR). Although several ligands have been shown to bind gp330 in solid-phase assays, the ability of gp330 to mediate ligand endocytosis has not been demonstrated. To develop a cellular model for gp330 function we screened a variety of cultured cell lines and identified several that expressed this protein, including immortalized rat type II pneumocytes and a human and two rodent tumor cell lines. Using type II pneumocytes, endocytosis of a previously described gp330 ligand, urokinase (uPA) complexed with plasminogen activator inhibitor-1 (uPA:PAI-1) and two new ligands, PAI-1 and pro-uPA, was demonstrated. RAP, the 39 kDa receptor-associated protein known to antagonize ligand binding to gp330 in solid-phase binding assays, completely inhibited both internalization and degradation of the radiolabeled ligands by type II pneumocytes. This suggested that the clearance of these ligands was dependent on either gp330 or the LDLR-related protein (LRP), which shares several ligand-binding characteristics with gp330. By using polyclonal antibodies to gp330, the cellular internalization and degradation of the ligands were inhibited by 30–50%; remaining ligand internalization and degradation activity could be partially inhibited by polyclonal antibodies against LRP. These findings indicate that gp330, like other LDLR family members, mediates endocytosis of its ligands. In addition, gp330 acts in concert with LRP in type II pneumocytes to mediate clearance of a variety of proteins involved in plasminogen activation, including uPA:PAI-1 complexes PAI-1 and pro-uPA.(ABSTRACT TRUNCATED AT 250 WORDS)

APA, Harvard, Vancouver, ISO, and other styles

17

Marsh, Lorraine. "Strong Ligand-Protein Interactions Derived from Diffuse Ligand Interactions with Loose Binding Sites." BioMed Research International 2015 (2015): 1–6. http://dx.doi.org/10.1155/2015/746980.

Full text

Abstract:

Many systems in biology rely on binding of ligands to target proteins in a single high-affinity conformation with a favorableΔG. Alternatively, interactions of ligands with protein regions that allow diffuse binding, distributed over multiple sites and conformations, can exhibit favorableΔGbecause of their higher entropy. Diffuse binding may be biologically important for multidrug transporters and carrier proteins. A fine-grained computational method for numerical integration of total bindingΔGarising from diffuse regional interaction of a ligand in multiple conformations using a Markov Chain Monte Carlo (MCMC) approach is presented. This method yields a metric that quantifies the influence on overall ligand affinity of ligand binding to multiple, distinct sites within a protein binding region. This metric is essentially a measure of dispersion in equilibrium ligand binding and depends on both the number of potential sites of interaction and the distribution of their individual predicted affinities. Analysis of test cases indicates that, for some ligand/protein pairs involving transporters and carrier proteins, diffuse binding contributes greatly to total affinity, whereas in other cases the influence is modest. This approach may be useful for studying situations where “nonspecific” interactions contribute to biological function.

APA, Harvard, Vancouver, ISO, and other styles

18

Srb, Pavel, Michal Svoboda, Ladislav Benda, Martin Lepšík, Ján Tarábek, Václav Šícha, Bohumír Grüner, et al. "Capturing a dynamically interacting inhibitor by paramagnetic NMR spectroscopy." Physical Chemistry Chemical Physics 21, no. 10 (2019): 5661–73. http://dx.doi.org/10.1039/c9cp00416e.

Full text

APA, Harvard, Vancouver, ISO, and other styles

19

Nero, Tracy L., Michael W. Parker, and Craig J. Morton. "Protein structure and computational drug discovery." Biochemical Society Transactions 46, no. 5 (September 21, 2018): 1367–79. http://dx.doi.org/10.1042/bst20180202.

Full text

Abstract:

The first protein structures revealed a complex web of weak interactions stabilising the three-dimensional shape of the molecule. Small molecule ligands were then found to exploit these same weak binding events to modulate protein function or act as substrates in enzymatic reactions. As the understanding of ligand–protein binding grew, it became possible to firstly predict how and where a particular small molecule might interact with a protein, and then to identify putative ligands for a specific protein site. Computer-aided drug discovery, based on the structure of target proteins, is now a well-established technique that has produced several marketed drugs. We present here an overview of the various methodologies being used for structure-based computer-aided drug discovery and comment on possible future developments in the field.

APA, Harvard, Vancouver, ISO, and other styles

20

Rother, Kristian, Mathias Dunkel, Elke Michalsky, Silke Trissl, Andrean Goede, Ulf Leser, and Robert Preissner. "A structural keystone for drug design." Journal of Integrative Bioinformatics 3, no. 1 (June 1, 2006): 21–31. http://dx.doi.org/10.1515/jib-2006-19.

Full text

Abstract:

Abstract 3D-structures of proteins and potential ligands are the cornerstones of rational drug design. The first brick to build upon is selecting a protein target and finding out whether biologically active compounds are known. Both tasks require more information than the structures themselves provide. For this purpose we have built a web resource bridging protein and ligand databases. It consists of three parts: i) A data warehouse on annotation of protein structures that integrates many well-known databases such as Swiss-Prot, SCOP, ENZYME and others. ii) A conformational library of structures of approved drugs. iii) A conformational library of ligands from the PDB, linking the realms of proteins and small molecules. The data collection contains structures of 30,000 proteins, 5,000 different ligands from 70,000 ligand-protein complexes, and 2,500 known drugs. Sets of protein structures can be refined by criteria like protein fold, family, metabolic pathway, resolution and textual annotation. The structures of organic compounds (drugs and ligands) can be searched considering chemical formula, trivial and trade names as well as medical classification codes for drugs (ATC). Retrieving structures by 2D-similarity has been implemented for all small molecules using Tanimoto coefficients. For the drug structures, 110,000 structural conformers have been calculated to account for structural flexibility. Two substances can be compared online by 3D-superimposition, where the pair of conformers that fits best is detected. Together, these web-accessible resources can be used to identify promising drug candidates. They have been used in-house to find alternatives to substances with a known binding activity but adverse side effects.

APA, Harvard, Vancouver, ISO, and other styles

21

Emsley, Paul. "Protein-Ligand Analysis and Validation." Acta Crystallographica Section A Foundations and Advances 70, a1 (August 5, 2014): C1480. http://dx.doi.org/10.1107/s2053273314085192.

Full text

Abstract:

A number of tools related to handling of ligands have been added to Coot in recent years - these include 2D depictions, ligand binding pocket layout and a ligand scoring system. Coot also incorporates a number interface to other tools (CCP4's Refmac, Molprobity's probe and reduce and the CCDC's Mogul) to generate score for protein ligand complexes. This scoring system has been applied to models (with data) from the PDB. The details of the ligand scoring, and its application to one's own complex structure will be discussed.

APA, Harvard, Vancouver, ISO, and other styles

22

Devgan, Manish. "STRUCTURE PREDICTION AND IN SILICO DESIGNING OF DRUGS AGAINST KALLIKREIN PROTEIN 12." International Journal of Current Pharmaceutical Research 9, no. 2 (March 1, 2017): 64. http://dx.doi.org/10.22159/ijcpr.2017v9i2.17387.

Full text

Abstract:

Objective: Human Kallikrein protein 12 (hK12) might serve as a novel diagnostic and prognostic biomarker, as well as a potential therapeutic target, in gastric cancer.Methods: In this work, a theoretical model of hK12 receptor protein was generated using the concepts of homology modeling and loop modeling. The resulting model was validated with Ramachandran plot analysis. The ligands generated with the help of Drug bank were docked against hK12 receptor protein using AutoDock Vina in PyRx 0.8. The structure of ligand DB04786 (Suramin), with least binding energy, was varied by using ACD/ChemSketch 8.0 and the docking was done for the resulting 16 new ligands.Results: The results indicated that the ligand10 bears the minimum binding energy (-12.3 Kcal/mol) with the target protein and thus the prospects of binding are high. The results also clearly demonstrated that the in silico molecular docking studies of selected ligands, i.e., suramin, ligands 5, 6, 10 and 16 with hK12 protein exhibited favourable binding interactions and warranted.Conclusion: Further studies needed for the development of potent inhibitors for the overexpression of hK12 protein making the management of gastric cancer more efficient.

APA, Harvard, Vancouver, ISO, and other styles

23

Loftis, Alexander R., Genwei Zhang, Coralie Backlund, Anthony J. Quartararo, Novalia Pishesha, Cameron C. Hanna, Carly K. Schissel, et al. "An in vivo selection-derived d-peptide for engineering erythrocyte-binding antigens that promote immune tolerance." Proceedings of the National Academy of Sciences 118, no. 34 (August 20, 2021): e2101596118. http://dx.doi.org/10.1073/pnas.2101596118.

Full text

Abstract:

When displayed on erythrocytes, peptides and proteins can drive antigen-specific immune tolerance. Here, we investigated a straightforward approach based on erythrocyte binding to promote antigen-specific tolerance to both peptides and proteins. We first identified a robust erythrocyte-binding ligand. A pool of one million fully d-chiral peptides was injected into mice, blood cells were isolated, and ligands enriched on these cells were identified using nano-liquid chromatography–tandem mass spectrometry. One round of selection yielded a murine erythrocyte-binding ligand with an 80 nM apparent dissociation constant, Kd. We modified an 83-kDa bacterial protein and a peptide antigen derived from ovalbumin (OVA) with the identified erythrocyte-binding ligand. An administration of the engineered bacterial protein led to decreased protein-specific antibodies in mice. Similarly, mice given the engineered OVA-derived peptide had decreased inflammatory anti-OVA CD8+ T cell responses. These findings suggest that our tolerance-induction strategy is applicable to both peptide and protein antigens and that our in vivo selection strategy can be used for de novo discovery of robust erythrocyte-binding ligands.

APA, Harvard, Vancouver, ISO, and other styles

24

Lu, Sumin, Wonjo Jang, Asuka Inoue, and Nevin A. Lambert. "Constitutive G protein coupling profiles of understudied orphan GPCRs." PLOS ONE 16, no. 4 (April 22, 2021): e0247743. http://dx.doi.org/10.1371/journal.pone.0247743.

Full text

Abstract:

A large number of GPCRs are potentially valuable drug targets but remain understudied. Many of these lack well-validated activating ligands and are considered “orphan” receptors, and G protein coupling profiles have not been defined for many orphan GPCRs. Here we asked if constitutive receptor activity can be used to determine G protein coupling profiles of orphan GPCRs. We monitored nucleotide-sensitive interactions between 48 understudied orphan GPCRs and five G proteins (240 combinations) using bioluminescence resonance energy transfer (BRET). No receptor ligands were used, but GDP was used as a common G protein ligand to disrupt receptor-G protein complexes. Constitutive BRET between the same receptors and β-arrestins was also measured. We found sufficient GDP-sensitive BRET to generate G protein coupling profiles for 22 of the 48 receptors we studied. Altogether we identified 48 coupled receptor-G protein pairs, many of which have not been described previously. We conclude that receptor-G protein complexes that form spontaneously in the absence of guanine nucleotides can be used to profile G protein coupling of constitutively-active GPCRs. This approach may prove useful for studying G protein coupling of other GPCRs for which activating ligands are not available.

APA, Harvard, Vancouver, ISO, and other styles

25

Kuznetsov, Aleksei, and Jaak Järv. "Ligand structure controlled allostery in cAMP-dependent protein kinase catalytic subunit." Open Life Sciences 4, no. 2 (June 1, 2009): 131–41. http://dx.doi.org/10.2478/s11535-009-0012-6.

Full text

Abstract:

AbstractProtein kinase A (cAMP dependent protein kinase catalytic subunit, EC 2.7.11.11) binds simultaneously ATP and a phosphorylatable peptide. These structurally dissimilar allosteric ligands influence the binding effectiveness of each other. The same situation is observed with substrate congeners, which reversibly inhibit the enzyme. In this review these allosteric effects are quantified using the interaction factor, which compares binding effectiveness of ligands with the free enzyme and the pre-loaded enzyme complex containing another ligand. This analysis revealed that the allosteric effect depends upon structure of the interacting ligands, and the principle “better binding: stronger allostery” observed can be formalized in terms of linear free-energy relationships, which point to similar mechanism of the allosteric interaction between the enzyme-bound substrates and/or inhibitor molecules. On the other hand, the type of effect is governed by ligand binding effectiveness and can be inverted from positive allostery to negative allostery if we move from effectively binding ligands to badly binding compounds. Thus the outcome of the allostery in this monomeric enzyme is the same as defined by classical theories for multimeric enzymes: making the enzyme response more efficient if appropriate ligands bind.

APA, Harvard, Vancouver, ISO, and other styles

26

Jayanna, P. K., D. Bedi, P. Deinnocentes, R. C. Bird, and V. A. Petrenko. "Landscape phage ligands for PC3 prostate carcinoma cells." Protein Engineering Design and Selection 23, no. 6 (February 25, 2010): 423–30. http://dx.doi.org/10.1093/protein/gzq011.

Full text

APA, Harvard, Vancouver, ISO, and other styles

27

Kurumatani, Natsumi, Hiroyuki Monji, and Takenao Ohkawa. "Binding Site Extraction by Similar Subgraphs Mining from Protein Molecular Surfaces and Its Application to Protein Classification." International Journal on Artificial Intelligence Tools 23, no. 03 (May 28, 2014): 1460007. http://dx.doi.org/10.1142/s0218213014600070.

Full text

Abstract:

Most proteins express their functions by binding with other proteins or molecular compounds (ligands). Since the characteristics of the local portion involved in binding (binding site) often determine the function of the protein, clarifying the location of the binding site of the protein helps analyze the function of proteins. Binding sites that bind to similar ligands often have common surface structures (surface motifs). Extracting the surface motifs among several proteins with similar functions improves binding site prediction. We propose a method that predicts binding sites by extracting the surface motifs that are frequently observed in only a specific set of proteins that bind to the same ligand (group). Since most binding sites have concave structures (pockets), the pockets are compared and common structures are searched for to extract the surface motifs by applying similar graph mining to the pocket data, which are represented as graphs. Common binding sites across several groups can be predicted in such a way to integrate more than one group. We also proposed a method of protein classification, in which the surface motifs extracted using the above method are evaluated on the assumption that a protein belongs to each one of the groups.

APA, Harvard, Vancouver, ISO, and other styles

28

Piekarska, B., J. Rybarska, B. Stopa, G. Zemanek, M. Król, I. Roterman, and L. Konieczny. "Supramolecularity creates nonstandard protein ligands." Acta Biochimica Polonica 46, no. 4 (December 31, 1999): 841–51. http://dx.doi.org/10.18388/abp.1999_4105.

Full text

Abstract:

Congo red and a group of structurally related dyes long used to stain amyloid proteins are known to associate in water solutions. The self-association of some dyes belonging to this group appears particularly strong. In water solutions their molecules are arranged in ribbon-like micellar forms with liquid crystalline properties. These compounds have recently been found to form complexes with some native proteins in a non-standard way. Gaps formed by the local distribution of beta-sheets in proteins probably represent the receptor sites for these dye ligands. They may result from higher structural instability in unfolding conditions, but also may appear as long range cooperative fluctuations generated by ligand binding. Immunoglobulins G were chosen as model binding proteins to check the mechanism of binding of these dyes. The sites of structural changes generated by antigen binding in antibodies, believed to act as a signal propagated to distant parts of the molecule, were assumed to be suitable sites for the complexation of liquid-crystalline dyes. This assumption was confirmed by proving that antibodies engaged in immune complexation really do bind these dyes; as expected, this binding affects their function by significantly enhancing antigen binding and simultaneously inhibiting C1q attachment. Binding of these supramolecular dyes by some other native proteins including serpins and their natural complexes was also shown. The strict dependence of the ligation properties on strong self-assembling and the particular arrangement of dye molecules indicate that supramolecularity is the feature that creates non-standard protein ligands, with potential uses in medicine and experimental science.

APA, Harvard, Vancouver, ISO, and other styles

29

Senisterra, Guillermo A., Hamed Ghanei, Galina Khutoreskaya, Elena Dobrovetsky, Aled M. Edwards, Gilbert G. Privé, and Masoud Vedadi. "Assessing the Stability of Membrane Proteins to Detect Ligand Binding Using Differential Static Light Scattering." Journal of Biomolecular Screening 15, no. 3 (February 11, 2010): 314–20. http://dx.doi.org/10.1177/1087057109357117.

Full text

Abstract:

Protein stabilization upon ligand binding has frequently been used to identify ligands for soluble proteins. Methods such as differential scanning fluorimetry (DSF) and differential static light scattering (DSLS) have been employed in the 384-well format and have been useful in identifying ligands that promote crystallization and 3D structure determination of proteins. However, finding a generic method that is applicable to membrane proteins has been a challenge as the high hydrophobicity of membrane proteins and the presence of detergents essential for their solubilization interfere with fluorescence-based detections. Here the authors used MsbA (an adenosine triphosphate binding cassette transporter), CorA (a Mg++ channel), and CpxA (a histidine kinase) as model proteins and show that DSLS is not sensitive to the presence of detergents or protein hydrophobicity and can be used to monitor thermodenaturation of membrane proteins, assess their stability, and detect ligand binding in a 384-well format.

APA, Harvard, Vancouver, ISO, and other styles

30

Whitesides, George M., and Vijay M. Krishnamurthy. "Designing ligands to bind proteins." Quarterly Reviews of Biophysics 38, no. 4 (November 2005): 385–95. http://dx.doi.org/10.1017/s0033583506004240.

Full text

Abstract:

The ability to design drugs (so-called ‘rational drug design’) has been one of the long-term objectives of chemistry for 50 years. It is an exceptionally difficult problem, and many of its parts lie outside the expertise of chemistry. The much more limited problem – how to design tight-binding ligands (rational ligand design) – would seem to be one that chemistry could solve, but has also proved remarkably recalcitrant. The question is ‘Why is it so difficult?’ and the answer is ‘We still don't entirely know’. This perspective discusses some of the technical issues – potential functions, protein plasticity, enthalpy/entropy compensation, and others – that contribute, and suggests areas where fundamental understanding of protein–ligand interactions falls short of what is needed. It surveys recent technological developments (in particular, isothermal titration calorimetry) that will, hopefully, make now the time for serious progress in this area. It concludes with the calorimetric examination of the association of a series of systematically varied ligands with a model protein. The counterintuitive thermodynamic results observed serve to illustrate that, even in relatively simple systems, understanding protein–ligand association is challenging.

APA, Harvard, Vancouver, ISO, and other styles

31

Rosa, Matthew, Timothy Noel, Matthew Harris, and Graham Ladds. "Emerging roles of adhesion G protein-coupled receptors." Biochemical Society Transactions 49, no. 4 (July 20, 2021): 1695–709. http://dx.doi.org/10.1042/bst20201144.

Full text

Abstract:

Adhesion G protein-coupled receptors (aGPCRs) form a sub-group within the GPCR superfamily. Their distinctive structure contains an abnormally large N-terminal, extracellular region with a GPCR autoproteolysis-inducing (GAIN) domain. In most aGPCRs, the GAIN domain constitutively cleaves the receptor into two fragments. This process is often required for aGPCR signalling. Over the last two decades, much research has focussed on aGPCR-ligand interactions, in an attempt to deorphanize the family. Most ligands have been found to bind to regions N-terminal to the GAIN domain. These receptors may bind a variety of ligands, ranging across membrane-bound proteins and extracellular matrix components. Recent advancements have revealed a conserved method of aGPCR activation involving a tethered ligand within the GAIN domain. Evidence for this comes from increased activity in receptor mutants exposing the tethered ligand. As a result, G protein-coupling partners of aGPCRs have been more extensively characterised, making use of their tethered ligand to create constitutively active mutants. This has led to demonstrations of aGPCR function in, for example, neurodevelopment and tumour growth. However, questions remain around the ligands that may bind many aGPCRs, how this binding is translated into changes in the GAIN domain, and the exact mechanism of aGPCR activation following GAIN domain conformational changes. This review aims to examine the current knowledge around aGPCR activation, including ligand binding sites, the mechanism of GAIN domain-mediated receptor activation and how aGPCR transmembrane domains may relate to activation. Other aspects of aGPCR signalling will be touched upon, such as downstream effectors and physiological roles.

APA, Harvard, Vancouver, ISO, and other styles

32

Ortiz-Muñoz, Andrés, Héctor F. Medina-Abarca, and Walter Fontana. "Combinatorial protein–protein interactions on a polymerizing scaffold." Proceedings of the National Academy of Sciences 117, no. 6 (January 24, 2020): 2930–37. http://dx.doi.org/10.1073/pnas.1912745117.

Full text

Abstract:

Scaffold proteins organize cellular processes by bringing signaling molecules into interaction, sometimes by forming large signalosomes. Several of these scaffolds are known to polymerize. Their assemblies should therefore not be understood as stoichiometric aggregates, but as combinatorial ensembles. We analyze the combinatorial interaction of ligands loaded on polymeric scaffolds, in both a continuum and discrete setting, and compare it with multivalent scaffolds with fixed number of binding sites. The quantity of interest is the abundance of ligand interaction possibilities—the catalytic potential Q—in a configurational mixture. Upon increasing scaffold abundance, scaffolding systems are known to first increase opportunities for ligand interaction and then to shut them down as ligands become isolated on distinct scaffolds. The polymerizing system stands out in that the dependency of Q on protomer concentration switches from being dominated by a first order to a second order term within a range determined by the polymerization affinity. This behavior boosts Q beyond that of any multivalent scaffold system. In addition, the subsequent drop-off is considerably mitigated in that Q decreases with half the power in protomer concentration than for any multivalent scaffold. We explain this behavior in terms of how the concentration profile of the polymer-length distribution adjusts to changes in protomer concentration and affinity. The discrete case turns out to be similar, but the behavior can be exaggerated at small protomer numbers because of a maximal polymer size, analogous to finite-size effects in bond percolation on a lattice.

APA, Harvard, Vancouver, ISO, and other styles

33

Siligardi, Giuliano, Charlotte S. Hughes, and Rohanah Hussain. "Characterisation of sensor kinase by CD spectroscopy: golden rules and tips." Biochemical Society Transactions 46, no. 6 (December 4, 2018): 1627–42. http://dx.doi.org/10.1042/bst20180222.

Full text

Abstract:

This is a review that describes the golden rules and tips on how to characterise the molecular interactions of membrane sensor kinase proteins with ligands using mainly circular dichroism (CD) spectroscopy. CD spectroscopy is essential for this task as any conformational change observed in the far-UV (secondary structures (α-helix, β-strands, poly-proline of type II, β-turns, irregular and folding) and near-UV regions [local environment of the aromatic side-chains of amino acid residues (Phe, Tyr and Trp) and ligands (drugs) and prosthetic groups (porphyrins, cofactors and coenzymes (FMN, FAD, NAD))] upon ligand addition to the protein can be used to determine qualitatively and quantitatively ligand-binding interactions. Advantages of using CD versus other techniques will be discussed. The difference CD spectra of the protein–ligand mixtures calculated subtracting the spectra of the ligand at various molar ratios can be used to determine the type of conformational changes induced by the ligand in terms of the estimated content of the various elements of protein secondary structure. The highly collimated microbeam and high photon flux of Diamond Light Source B23 beamline for synchrotron radiation circular dichroism (SRCD) enable the use of minimal amount of membrane proteins (7.5 µg for a 0.5 mg/ml solution) for high-throughput screening. Several examples of CD titrations of membrane proteins with a variety of ligands are described herein including the protocol tips that would guide the choice of the appropriate parameters to conduct these titrations by CD/SRCD in the best possible way.

APA, Harvard, Vancouver, ISO, and other styles

34

Logie, Colin, Mark Nichols, Kathy Myles, John W. Funder, and A. Francis Stewart. "Positive and Negative Discrimination of Estrogen Receptor Agonists and Antagonists Using Site-Specific DNA Recombinase Fusion Proteins." Molecular Endocrinology 12, no. 8 (August 1, 1998): 1120–32. http://dx.doi.org/10.1210/mend.12.8.0155.

Full text

Abstract:

Abstract Activation of the estrogen receptor (ER) by hormone involves at least two steps. First, hormone binding initially relieves repression, a property imposed on ER in cis by its ligand-binding domain (EBD). Subsequently, the derepressed ER binds specific genomic sites and regulates transcription. In addition to the natural hormone, ER binds a broad range of ligands that evoke a spectrum of responses ranging from full ER activation by agonists to partial activation and inhibition by partial or complete antagonists. How these different ligands evoke different ER responses remains unclear. To address this issue, we have developed a nontranscriptional assay for ER ligand responsiveness based on Flp recombinase/human EBD protein chimeras. These fusion proteins transduce the transient event of ligand binding into a permanent DNA change in a human cell line system. A fusion protein including ER D, E, and F domains was activated by all the ER ligands tested, demonstrating that both agonists and antagonists serve to relieve initial repression, and that differences between them lie downstream in the activation pathway. Mutant variants of the Flp-ER protein that distinguish between agonists and antagonists, and a mutant EBD that selectively lost the ability to respond to 17β-estradiol but not to other ligands, were also identified. Thus, agonists and antagonists can be functionally distinguished in a nontranscriptional assay.

APA, Harvard, Vancouver, ISO, and other styles

35

Borodin, E. A., A. P. Chupalov, P. D. Timkin, E. A. Timofeev, and N. Yu Leusova. "Selection of potential ligands for TRPM8 using deep neural networks and intermolecular docking." Bulletin Physiology and Pathology of Respiration, no. 80 (July 16, 2021): 26–33. http://dx.doi.org/10.36604/1998-5029-2021-80-26-33.

Full text

Abstract:

Introduction. TRPM8 has been implicated in the development of bronchial hypersensitivity to cold and is considered a potential target for computer-generated drugs.Aim. Development of a strategy for the selection of ligands for TRPM8 by in silico methods.Materials and methods. Using machine learning tools based on deep neural networks and further verification by intermolecular docking, a strategy has been proposed for predicting potential ligands for TRPM8, which consists in using a neural network to screen out potential drug candidates and thereby reduce the list of candidate ligands for verification using AutoDock program, which allows assessing the affinity of a protein for a ligand by the minimum binding energy and identifying possible conformations of a ligand upon binding to certain centers (amino acid residues) of a protein. The latter were used: Y745 (tyrosine 745 is a critical center for TRPM8), R1008 (phenylalanine 1008) and L1009 (alanine 1009).Results. Of the 10 potential ligands predicted by the neural network, eight showed a high minimum binding energy and a greater number of conformations compared to the classic TRPM8 ligand, menthol, when verified by the AutoDock program. The two predicted ligands did not show the ability to interact with TRPM8, which may be due to insufficient allocated memory of the computing device for successful docking or other technical problems.Conclusion. The proposed strategy is universal; it will accelerate the search for ligands for various proteins and will facilitate the accelerated search for potential drugs by in silico methods.

APA, Harvard, Vancouver, ISO, and other styles

36

Perkins, Stephen J., Azubuike I. Okemefuna, and Ruodan Nan. "Unravelling protein–protein interactions between complement factor H and C-reactive protein using a multidisciplinary strategy." Biochemical Society Transactions 38, no. 4 (July 26, 2010): 894–900. http://dx.doi.org/10.1042/bst0380894.

Full text

Abstract:

Experimental studies of protein–protein interactions are very much affected by whether the complexes are fully formed (strong, with nanomolar dissociation constants) or partially dissociated (weak, with micromolar dissociation constants). The functions of the complement proteins of innate immunity are governed by the weak interactions between the activated proteins and their regulators. Complement is effective in attacking pathogens, but not the human host, and imbalances in this process can lead to disease conditions. The inherent complexity in analysing complement interactions is augmented by the multivalency of its main regulator, CFH (complement factor H), for its physiological or pathophysiological ligands. The unravelling of such weak protein–protein or protein–ligand interactions requires a multidisciplinary approach. Synchrotron X-ray solution scattering and constrained modelling resulted in the determination of the solution structure of CFH and its self-associative properties, whereas AUC (analytical ultracentrifugation) identified the formation of much larger CFH multimers through the addition of metals such as zinc. The ligands of CFH, such as CRP (C-reactive protein), also undergo self-association. The combination of X-rays and AUC with SPR (surface plasmon resonance) proved to be essential to identify CRP self-association and revealed how CFH interacts with CRP. We show that CRP unexpectedly binds to CFH at two non-contiguous sites and explain its relevance to age-related macular degeneration.

APA, Harvard, Vancouver, ISO, and other styles

37

Schmidt, Uli, Rainer Rudolph, and Gerald Böhm. "Binding of external ligands onto an engineered virus capsid." Protein Engineering, Design and Selection 14, no. 10 (October 2001): 769–74. http://dx.doi.org/10.1093/protein/14.10.769.

Full text

APA, Harvard, Vancouver, ISO, and other styles

38

Sylte, Ingebrigt, Øyvind Edvardsen, and Svein G. Dahl. "Molecular dynamics of the 5-HT1a receptor and ligands." "Protein Engineering, Design and Selection" 6, no. 7 (1993): 691–700. http://dx.doi.org/10.1093/protein/6.7.691.

Full text

APA, Harvard, Vancouver, ISO, and other styles

39

Wikman, M., A. C. Steffen, E. Gunneriusson, V. Tolmachev, G. P. Adams, J. Carlsson, and S. Stahl. "Selection and characterization of HER2/neu-binding affibody ligands." Protein Engineering Design and Selection 17, no. 5 (June 8, 2004): 455–62. http://dx.doi.org/10.1093/protein/gzh053.

Full text

APA, Harvard, Vancouver, ISO, and other styles

40

Bemister-Buffington, Joseph, Alex J. Wolf, Sebastian Raschka, and Leslie A. Kuhn. "Machine Learning to Identify Flexibility Signatures of Class A GPCR Inhibition." Biomolecules 10, no. 3 (March 14, 2020): 454. http://dx.doi.org/10.3390/biom10030454.

Full text

Abstract:

We show that machine learning can pinpoint features distinguishing inactive from active states in proteins, in particular identifying key ligand binding site flexibility transitions in GPCRs that are triggered by biologically active ligands. Our analysis was performed on the helical segments and loops in 18 inactive and 9 active class A G protein-coupled receptors (GPCRs). These three-dimensional (3D) structures were determined in complex with ligands. However, considering the flexible versus rigid state identified by graph-theoretic ProFlex rigidity analysis for each helix and loop segment with the ligand removed, followed by feature selection and k-nearest neighbor classification, was sufficient to identify four segments surrounding the ligand binding site whose flexibility/rigidity accurately predicts whether a GPCR is in an active or inactive state. GPCRs bound to inhibitors were similar in their pattern of flexible versus rigid regions, whereas agonist-bound GPCRs were more flexible and diverse. This new ligand-proximal flexibility signature of GPCR activity was identified without knowledge of the ligand binding mode or previously defined switch regions, while being adjacent to the known transmission switch. Following this proof of concept, the ProFlex flexibility analysis coupled with pattern recognition and activity classification may be useful for predicting whether newly designed ligands behave as activators or inhibitors in protein families in general, based on the pattern of flexibility they induce in the protein.

APA, Harvard, Vancouver, ISO, and other styles

41

Copoiu, Liviu, Pedro H. M. Torres, David B. Ascher, Tom L. Blundell, and Sony Malhotra. "ProCarbDB: a database of carbohydrate-binding proteins." Nucleic Acids Research 48, no. D1 (October 10, 2019): D368—D375. http://dx.doi.org/10.1093/nar/gkz860.

Full text

Abstract:

Abstract Carbohydrate-binding proteins play crucial roles across all organisms and viruses. The complexity of carbohydrate structures, together with inconsistencies in how their 3D structures are reported, has led to difficulties in characterizing the protein–carbohydrate interfaces. In order to better understand protein–carbohydrate interactions, we have developed an open-access database, ProCarbDB, which, unlike the Protein Data Bank (PDB), clearly distinguishes between the complete carbohydrate ligands and their monomeric units. ProCarbDB is a comprehensive database containing over 5200 3D X-ray crystal structures of protein–carbohydrate complexes. In ProCarbDB, the complete carbohydrate ligands are annotated and all their interactions are displayed. Users can also select any protein residue in the proximity of the ligand to inspect its interactions with the carbohydrate ligand and with other neighbouring protein residues. Where available, additional curated information on the binding affinity of the complex and the effects of mutations on the binding have also been provided in the database. We believe that ProCarbDB will be an invaluable resource for understanding protein–carbohydrate interfaces. The ProCarbDB web server is freely available at http://www.procarbdb.science/procarb.

APA, Harvard, Vancouver, ISO, and other styles

42

Narunsky, Aya, Amit Kessel, Ron Solan, Vikram Alva, Rachel Kolodny, and Nir Ben-Tal. "On the evolution of protein–adenine binding." Proceedings of the National Academy of Sciences 117, no. 9 (February 20, 2020): 4701–9. http://dx.doi.org/10.1073/pnas.1911349117.

Full text

Abstract:

Proteins’ interactions with ancient ligands may reveal how molecular recognition emerged and evolved. We explore how proteins recognize adenine: a planar rigid fragment found in the most common and ancient ligands. We have developed a computational pipeline that extracts protein–adenine complexes from the Protein Data Bank, structurally superimposes their adenine fragments, and detects the hydrogen bonds mediating the interaction. Our analysis extends the known motifs of protein–adenine interactions in the Watson–Crick edge of adenine and shows that all of adenine’s edges may contribute to molecular recognition. We further show that, on the proteins' side, binding is often mediated by specific amino acid segments (“themes”) that recur across different proteins, such that different proteins use the same themes when binding the same adenine-containing ligands. We identify numerous proteins that feature these themes and are thus likely to bind adenine-containing ligands. Our analysis suggests that adenine binding has emerged multiple times in evolution.

APA, Harvard, Vancouver, ISO, and other styles

43

Denton, Kyle E., Sijie Wang, Michael C. Gignac, Natalia Milosevich, Fraser Hof, Emily C. Dykhuizen, and Casey J. Krusemark. "Robustness of In Vitro Selection Assays of DNA-Encoded Peptidomimetic Ligands to CBX7 and CBX8." SLAS DISCOVERY: Advancing the Science of Drug Discovery 23, no. 5 (January 8, 2018): 417–28. http://dx.doi.org/10.1177/2472555217750871.

Full text

Abstract:

The identification of protein ligands from a DNA-encoded library is commonly conducted by an affinity selection assay. These assays are often not validated for robustness, raising questions about selections that fail to identify ligands and the utility of enrichment values for ranking ligand potencies. Here, we report a method for optimizing and utilizing affinity selection assays to identify potent and selective peptidic ligands to the highly related chromodomains of CBX proteins. To optimize affinity selection parameters, statistical analyses (Z′ factors) were used to define the ability of selection assay conditions to identify and differentiate ligands of varying affinity. A DNA-encoded positional scanning library of peptidomimetics was constructed around a trimethyllysine-containing parent peptide, and parallel selections against the chromodomains from CBX8 and CBX7 were conducted over three protein concentrations. Relative potencies of off-DNA hit molecules were determined through a fluorescence polarization assay and were consistent with enrichments observed by DNA sequencing of the affinity selection assays. In addition, novel peptide-based ligands were discovered with increased potency and selectivity to the chromodomain of CBX8. The results indicate low DNA tag bias and show that affinity-based in vitro selection assays are sufficiently robust for both ligand discovery and determination of quantitative structure–activity relationships.

APA, Harvard, Vancouver, ISO, and other styles

44

Gollan, Timothy J., and Michael R. Green. "Redirecting Retroviral Tropism by Insertion of Short, Nondisruptive Peptide Ligands into Envelope." Journal of Virology 76, no. 7 (April 1, 2002): 3558–63. http://dx.doi.org/10.1128/jvi.76.7.3558-3563.2002.

Full text

Abstract:

ABSTRACT A potentially powerful approach for in vivo gene delivery is to target retrovirus to specific cells through interactions between cell surface receptors and appropriately modified viral envelope proteins. Previously, relatively large (>100 residues) protein ligands to cell surface receptors have been inserted at or near the N terminus of retroviral envelope proteins. Although viral tropism could be altered, the chimeric envelope proteins lacked full activity, and coexpression of wild-type envelope was required for production of transducing virus. Here we analyze more than 40 derivatives of ecotropic Moloney murine leukemia virus (MLV) envelope, containing insertions of short RGD-containing peptides, which are ligands for integrin receptors. In many cases pseudotyped viruses containing only the chimeric envelope protein could transduce human cells. The precise location, size, and flanking sequences of the ligand affected transduction specificity and efficiency. We conclude that retroviral tropism can be rationally reengineered by insertion of short peptide ligands and without the need to coexpress wild-type envelope.

APA, Harvard, Vancouver, ISO, and other styles

45

Hendlich, Manfred. "Databases for Protein–Ligand Complexes." Acta Crystallographica Section D Biological Crystallography 54, no. 6 (November 1, 1998): 1178–82. http://dx.doi.org/10.1107/s0907444998007124.

Full text

Abstract:

Recent advances in experimental techniques have led to an enormous explosion of available data about protein–ligand complexes. To exploit the information that is hidden in these large data, collection tools for managing and accessing huge data collections are needed. This paper discusses databases for protein–ligand data which are accessibleviathe World Wide Web. A strong focus is placed on the ReLiBase database system which is a new three-dimensional database for storing and analysing structures of protein–ligand complexes currently deposited in the Brookhaven Protein Data Bank (PDB). ReLiBase contains efficient query tools for identifying and analysing ligands and protein–ligand complexes. Its application for structure-based drug design is illustrated.

APA, Harvard, Vancouver, ISO, and other styles

46

Kobren, Shilpa Nadimpalli, and Mona Singh. "Systematic domain-based aggregation of protein structures highlights DNA-, RNA- and other ligand-binding positions." Nucleic Acids Research 47, no. 2 (December 7, 2018): 582–93. http://dx.doi.org/10.1093/nar/gky1224.

Full text

Abstract:

Abstract Domains are fundamental subunits of proteins, and while they play major roles in facilitating protein–DNA, protein–RNA and other protein–ligand interactions, a systematic assessment of their various interaction modes is still lacking. A comprehensive resource identifying positions within domains that tend to interact with nucleic acids, small molecules and other ligands would expand our knowledge of domain functionality as well as aid in detecting ligand-binding sites within structurally uncharacterized proteins. Here, we introduce an approach to identify per-domain-position interaction ‘frequencies’ by aggregating protein co-complex structures by domain and ascertaining how often residues mapping to each domain position interact with ligands. We perform this domain-based analysis on ∼91000 co-complex structures, and infer positions involved in binding DNA, RNA, peptides, ions or small molecules across 4128 domains, which we refer to collectively as the InteracDome. Cross-validation testing reveals that ligand-binding positions for 2152 domains are highly consistent and can be used to identify residues facilitating interactions in ∼63–69% of human genes. Our resource of domain-inferred ligand-binding sites should be a great aid in understanding disease etiology: whereas these sites are enriched in Mendelian-associated and cancer somatic mutations, they are depleted in polymorphisms observed across healthy populations. The InteracDome is available at http://interacdome.princeton.edu.

APA, Harvard, Vancouver, ISO, and other styles

47

Berezhkovskii, Alexander M., Dah-Yen Yang, Sheh-Yi Sheu, and Sheng Hsien Lin. "Stochastic gating in diffusion-influenced ligand binding to proteins: Gated protein versus gated ligands." Physical Review E 54, no. 4 (October 1, 1996): 4462–64. http://dx.doi.org/10.1103/physreve.54.4462.

Full text

APA, Harvard, Vancouver, ISO, and other styles

48

Calderone, Richard A. "Recognition of endothelial cells byCandida albicans: role of complement-binding proteins." Canadian Journal of Botany 73, S1 (December 31, 1995): 1154–59. http://dx.doi.org/10.1139/b95-372.

Full text

Abstract:

Candida albicans, a commensal of humans, can cause either mucosal or systemic infections. The virulence properties of the organism include cell-surface adhesins that recognize ligands of host cells. Hyphal forms of the organism possess a 60-kDa mannoprotein that recognizes a variety of host-cell ligands including the complement C3 conversion products, C3bi and C3d. In addition, a protein of similar molecular mass also binds to endothelial extracellular matrix proteins such as laminin and fibronectin. While the 60-kDa protein is associated with the cell surface of hyphal forms of the organism, a protein of 50 kDa with similar ligand-binding activities is associated with the plasma membrane of blastoconidia. This protein cross reacts with antibodies to the 60-kDa protein. Isolation of the gene(s) encoding these cell-surface proteins is underway using both a human B-lymphocyte CR2 gene fragment or oligonucleotides based upon peptide sequence to screen libraries of C. albicans. Mutants of the organism with reduced expression of either C3d or C3bi-binding activity have been isolated. These strains are less virulent and also less adherent in vitro. Studies are currently underway to define the contribution of these proteins to the virulence of the organism. Key words: adherence, complement receptor, mannoprotein, virulence, ligand recognition.

APA, Harvard, Vancouver, ISO, and other styles

49

Brzezinski, Dariusz, Przemyslaw J. Porebski, Marcin Kowiel, Joanna M. Macnar, and Wladek Minor. "Recognizing and validating ligands with CheckMyBlob." Nucleic Acids Research 49, W1 (April 27, 2021): W86—W92. http://dx.doi.org/10.1093/nar/gkab296.

Full text

Abstract:

Abstract Structure-guided drug design depends on the correct identification of ligands in crystal structures of protein complexes. However, the interpretation of the electron density maps is challenging and often burdened with confirmation bias. Ligand identification can be aided by automatic methods such as CheckMyBlob, a machine learning algorithm that learns to generalize ligand descriptions from sets of moieties deposited in the Protein Data Bank. Here, we present the CheckMyBlob web server, a platform that can identify ligands in unmodeled fragments of electron density maps or validate ligands in existing models. The server processes PDB/mmCIF and MTZ files and returns a ranking of 10 most likely ligands for each detected electron density blob along with interactive 3D visualizations. Additionally, for each prediction/validation, a plugin script is generated that enables users to conduct a detailed analysis of the server results in Coot. The CheckMyBlob web server is available at https://checkmyblob.bioreproducibility.org.

APA, Harvard, Vancouver, ISO, and other styles

50

Takahashi, Masaki, Ryo Amano, Michiru Ozawa, Anna Martinez, Kazumasa Akita, and Yoshikazu Nakamura. "Nucleic acid ligands act as a PAM and agonist depending on the intrinsic ligand binding state of P2RY2." Proceedings of the National Academy of Sciences 118, no. 18 (April 28, 2021): e2019497118. http://dx.doi.org/10.1073/pnas.2019497118.

Full text

Abstract:

G protein–coupled receptors (GPCRs) play diverse roles in physiological processes, and hence the ligands to modulate GPCRs have served as important molecules in biological and pharmacological approaches. However, the exploration of novel ligands for GPCR still remains an arduous challenge. In this study, we report a method for the discovery of nucleic acid ligands against GPCRs by an advanced RNA aptamer screening technology that employs a virus-like particle (VLP), exposing the GPCR of interest. An array of biochemical analyses coupled with a cell-based assay revealed that one of the aptamers raised against purinergic receptor P2Y2 (P2RY2), a GPCR, exhibits an activation potency to unliganded receptor and prohibits a further receptor activation by endogenous ligand, behaving like a partial agonist. However, the aptamer enhances the activity of intrinsic ligand-binding P2RY2, thereby acting as a positive allosteric modulator (PAM) to liganded receptor. Our findings demonstrate that the nucleic acid aptamer conditionally exerts PAM and agonist effects on GPCRs, depending on their intrinsic ligand binding state. These results indicate the validity of our VLP-based aptamer screening targeting GPCR and reemphasize the great potential of nucleic acid ligands for exploring the GPCR activation mechanism and therapeutic applications.

APA, Harvard, Vancouver, ISO, and other styles

Journal articles on the topic 'Protein; Ligands'

Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles