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Journal articles on the topic 'Ligand Recognition'

Author: Grafiati

Published: 6 September 2023

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1

Vijayrajratnam, Sukhithasri, Anju Choorakottayil Pushkaran, Aathira Balakrishnan, Anil Kumar Vasudevan, Raja Biswas, and Chethampadi Gopi Mohan. "Understanding the molecular differential recognition of muramyl peptide ligands by LRR domains of human NOD receptors." Biochemical Journal 474, no. 16 (July 27, 2017): 2691–711. http://dx.doi.org/10.1042/bcj20170220.

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Human nucleotide-binding oligomerization domain proteins, hNOD1 and hNOD2, are host intracellular receptors with C-terminal leucine-rich repeat (LRR) domains, which recognize specific bacterial peptidoglycan (PG) fragments as their ligands. The specificity of this recognition is dependent on the third amino acid of the stem peptide of the PG ligand, which is usually meso-diaminopimelic acid (mesoDAP) or l-lysine (l-Lys). Since the LRR domains of hNOD receptors had been experimentally shown to confer the PG ligand-sensing specificity, we developed three-dimensional structures of hNOD1-LRR and the hNOD2-LRR to understand the mechanism of differential recognition of muramyl peptide ligands by hNOD receptors. The hNOD1-LRR and hNOD2-LRR receptor models exhibited right-handed curved solenoid shape. The hot-spot residues experimentally proved to be critical for ligand recognition were located in the concavity of the NOD-LRR and formed the recognition site. Our molecular docking analyses and molecular electrostatic potential mapping studies explain the activation of hNOD-LRRs, in response to effective molecular interactions of PG ligands at the recognition site; and conversely, the inability of certain PG ligands to activate hNOD-LRRs, by deviations from the recognition site. Based on molecular docking studies using PG ligands, we propose few residues — G825, D826 and N850 in hNOD1-LRR and L904, G905, W931, L932 and S933 in hNOD2-LRR, evolutionarily conserved across different host species, which may play a major role in ligand recognition. Thus, our integrated experimental and computational approach elucidates the molecular basis underlying the differential recognition of PG ligands by hNOD receptors.

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Smyth, Mark J., Jeremy Swann, Janice M. Kelly, Erika Cretney, Wayne M. Yokoyama, Andreas Diefenbach, Thomas J. Sayers, and Yoshihiro Hayakawa. "NKG2D Recognition and Perforin Effector Function Mediate Effective Cytokine Immunotherapy of Cancer." Journal of Experimental Medicine 200, no. 10 (November 15, 2004): 1325–35. http://dx.doi.org/10.1084/jem.20041522.

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Single and combination cytokines offer promise in some patients with advanced cancer. Many spontaneous and experimental cancers naturally express ligands for the lectin-like type-2 transmembrane stimulatory NKG2D immunoreceptor; however, the role this tumor recognition pathway plays in immunotherapy has not been explored to date. Here, we show that natural expression of NKG2D ligands on tumors provides an effective target for some cytokine-stimulated NK cells to recognize and suppress tumor metastases. In particular, interleukin (IL)-2 or IL-12 suppressed tumor metastases largely via NKG2D ligand recognition and perforin-mediated cytotoxicity. By contrast, IL-18 required tumor sensitivity to Fas ligand (FasL) and surprisingly did not depend on the NKG2D–NKG2D ligand pathway. A combination of IL-2 and IL-18 stimulated both perforin and FasL effector mechanisms with very potent effects. Cytokines that stimulated perforin-mediated cytotoxicity appeared relatively more effective against tumor metastases expressing NKG2D ligands. These findings indicate that a rational choice of cytokines can be made given the known sensitivity of tumor cells to perforin, FasL, and tumor necrosis factor–related apoptosis-inducing ligand and the NKG2D ligand status of tumor metastases.

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Gasparri, Federica, Jesper Wengel, Thomas Grutter, and Stephan A. Pless. "Molecular determinants for agonist recognition and discrimination in P2X2 receptors." Journal of General Physiology 151, no. 7 (May 24, 2019): 898–911. http://dx.doi.org/10.1085/jgp.201912347.

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P2X receptors (P2XRs) are trimeric ligand-gated ion channels that open a cation-selective pore in response to ATP binding. P2XRs contribute to synaptic transmission and are involved in pain and inflammation, thus representing valuable drug targets. Recent crystal structures have confirmed the findings of previous studies with regards to the amino acid chains involved in ligand recognition, but they have also suggested that backbone carbonyl atoms contribute to ATP recognition and discrimination. Here we use a combination of site-directed mutagenesis, amide-to-ester substitutions, and a range of ATP analogues with subtle alterations to either base or sugar component to investigate the contributions of backbone carbonyl atoms toward ligand recognition and discrimination in rat P2X2Rs. Our findings demonstrate that while the Lys69 backbone carbonyl makes an important contribution to ligand recognition, the discrimination between different ligands is mediated by both the side chain and the backbone carbonyl oxygen of Thr184. Together, our data demonstrate how conserved elements in P2X2Rs recognize and discriminate agonists.

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Baron, Riccardo, and J. Andrew McCammon. "Molecular Recognition and Ligand Association." Annual Review of Physical Chemistry 64, no. 1 (April 2013): 151–75. http://dx.doi.org/10.1146/annurev-physchem-040412-110047.

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5

Baron, Riccardo, Piotr Setny, and J. Andrew McCammon. "Water in Cavity−Ligand Recognition." Journal of the American Chemical Society 132, no. 34 (August 9, 2010): 12091–97. http://dx.doi.org/10.1021/ja1050082.

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6

Anand, Praveen, Deepesh Nagarajan, Sumanta Mukherjee, and Nagasuma Chandra. "ABS–Scan: In silico alanine scanning mutagenesis for binding site residues in protein–ligand complex." F1000Research 3 (September 9, 2014): 214. http://dx.doi.org/10.12688/f1000research.5165.1.

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Most physiological processes in living systems are fundamentally regulated by protein–ligand interactions. Understanding the process of ligand recognition by proteins is a vital activity in molecular biology and biochemistry. It is well known that the residues present at the binding site of the protein form pockets that provide a conducive environment for recognition of specific ligands. In many cases, the boundaries of these sites are not well defined. Here, we provide a web-server to systematically evaluate important residues in the binding site of the protein that contribute towards the ligand recognition through in silico alanine-scanning mutagenesis experiments. Each of the residues present at the binding site is computationally mutated to alanine. The ligand interaction energy is computed for each mutant and the corresponding ΔΔG values are computed by comparing it to the wild type protein, thus evaluating individual residue contributions towards ligand interaction. The server will thus provide clues to researchers about residues to obtain loss-of-function mutations and to understand drug resistant mutations. This web-tool can be freely accessed through the following address: http://proline.biochem.iisc.ernet.in/abscan/.

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Anand, Praveen, Deepesh Nagarajan, Sumanta Mukherjee, and Nagasuma Chandra. "ABS–Scan: In silico alanine scanning mutagenesis for binding site residues in protein–ligand complex." F1000Research 3 (December 1, 2014): 214. http://dx.doi.org/10.12688/f1000research.5165.2.

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Most physiological processes in living systems are fundamentally regulated by protein–ligand interactions. Understanding the process of ligand recognition by proteins is a vital activity in molecular biology and biochemistry. It is well known that the residues present at the binding site of the protein form pockets that provide a conducive environment for recognition of specific ligands. In many cases, the boundaries of these sites are not well defined. Here, we provide a web-server to systematically evaluate important residues in the binding site of the protein that contribute towards the ligand recognition through in silico alanine-scanning mutagenesis experiments. Each of the residues present at the binding site is computationally mutated to alanine. The ligand interaction energy is computed for each mutant and the corresponding ΔΔG values are calculated by comparing it to the wild type protein, thus evaluating individual residue contributions towards ligand interaction. The server will thus provide a ranked list of residues to the user in order to obtain loss-of-function mutations. This web-tool can be freely accessed through the following address: http://proline.biochem.iisc.ernet.in/abscan/.

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8

McMillan, Jourdan K. P., Patrick O’Donnell, and Sandra P. Chang. "Pattern recognition receptor ligand-induced differentiation of human transitional B cells." PLOS ONE 17, no. 8 (August 30, 2022): e0273810. http://dx.doi.org/10.1371/journal.pone.0273810.

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B cells represent a critical component of the adaptive immune response whose development and differentiation are determined by antigen-dependent and antigen-independent interactions. In this study, we explored the effects of IL-4 and pattern-recognition receptor (PRR) ligands on B cell development and differentiation by investigating their capacity to drive the in vitro maturation of human transitional B cells. In the presence of IL-4, ligands for TLR7/8, TLR9, and NOD1 were effective in driving the in vitro maturation of cord blood transitional B cells into mature, naïve B cells as measured by CD23 expression, ABCB1 transporter activation and upregulation of sIgM and sIgD. In addition, several stimulation conditions, including TLR9 ligand alone, favored an expansion of CD27+ IgM memory B cells. Transitional B cells stimulated with TLR7/8 ligand + IL-4 or TLR9 ligand, with or without IL-4, induced a significant subpopulation of CD23+CD27+ B cells expressing high levels of sIgM and sIgD, a minor B cell subpopulation found in human peripheral blood. These studies illustrate the heterogeneity of the B cell populations induced by cytokine and PRR ligand stimulation. A comparison of transitional and mature, naïve B cells transcriptomes to identify novel genes involved in B cell maturation revealed that mature, naïve B cells were less transcriptionally active than transitional B cells. Nevertheless, a subset of differentially expressed genes in mature, naïve B cells was identified including genes associated with the IL-4 signaling pathway, PI3K signaling in B lymphocytes, the NF-κB signaling pathway, and the TNFR superfamily. When transitional B cells were stimulated in vitro with IL-4 and PRR ligands, gene expression was found to be dependent on the nature of the stimulants, suggesting that exposure to these stimulants may alter the developmental fate of transitional B cells. The influence of IL-4 and PRR signaling on transitional B cell maturation illustrates the potential synergy that may be achieved when certain PRR ligands are incorporated as adjuvants in vaccine formulations and presented to developing B cells in the context of an inflammatory cytokine environment. These studies demonstrate the potential of the PRR ligands to drive transitional B cell differentiation in the periphery during infection or vaccination independently of antigen mediated BCR signaling.

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Leboffe, Loris, Alessandra di Masi, Fabio Polticelli, Viviana Trezza, and Paolo Ascenzi. "Structural Basis of Drug Recognition by Human Serum Albumin." Current Medicinal Chemistry 27, no. 30 (September 8, 2020): 4907–31. http://dx.doi.org/10.2174/0929867326666190320105316.

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Background: Human serum albumin (HSA), the most abundant protein in plasma, is a monomeric multi-domain macromolecule with at least nine binding sites for endogenous and exogenous ligands. HSA displays an extraordinary ligand binding capacity as a depot and carrier for many compounds including most acidic drugs. Consequently, HSA has the potential to influence the pharmacokinetics and pharmacodynamics of drugs. Objective: In this review, the structural determinants of drug binding to the multiple sites of HSA are analyzed and discussed in detail. Moreover, insight into the allosteric and competitive mechanisms underpinning drug recognition, delivery, and efficacy are analyzed and discussed. Conclusion: As several factors can modulate drug binding to HSA (e.g., concurrent administration of drugs competing for the same binding site, ligand binding to allosteric-coupled clefts, genetic inherited diseases, and post-translational modifications), ligand binding to HSA is relevant not only under physiological conditions, but also in the pharmacological therapy management.

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Diamond, M. S., J. Garcia-Aguilar, J. K. Bickford, A. L. Corbi, and T. A. Springer. "The I domain is a major recognition site on the leukocyte integrin Mac-1 (CD11b/CD18) for four distinct adhesion ligands." Journal of Cell Biology 120, no. 4 (February 15, 1993): 1031–43. http://dx.doi.org/10.1083/jcb.120.4.1031.

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Despite the identification and characterization of several distinct ligands for the leukocyte integrin (CD11/CD18) family of adhesion receptors, little is known about the structural regions on these molecules that mediate ligand recognition. In this report, we use alpha subunit chimeras of Mac-1 (CD11b/CD18) and p150,95 (CD11c/CD18), and an extended panel of newly generated and previously characterized mAbs specific to the alpha chain of Mac-1 to map the binding sites for four distinct ligands for Mac-1: iC3b, fibrinogen, ICAM-1, and the as-yet uncharacterized counter-receptor responsible for neutrophil homotypic adhesion. Epitopes of mAbs that blocked ligand binding were mapped with the chimeras and used to localize the ligand recognition sites because the data obtained from functional assays with the Mac-1/p150,95 chimeras were not easily interpreted. Results show that the I domain on the alpha chain of Mac-1 is an important recognition site for all four ligands, and that the NH2-terminal and perhaps divalent cation binding regions but not the COOH-terminal segment may contribute. The recognition sites in the I domain appear overlapping but not identical as individual Mac-1-ligand interactions are distinguished by the discrete patterns of inhibitory mAbs. Additionally, we find that the alpha subunit NH2-terminal region and divalent cation binding region, despite being separated by over 200 amino acids of the I domain, appear structurally apposed because three mAbs require the presence of both of these regions for antigenic reactivity, and chimeras that contain the NH2 terminus of p150,95 require the divalent cation binding region of p150,95 to associate firmly with the beta subunit.

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11

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.

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12

Koehler, Melanie, Anny Fis, Hermann J. Gruber, and Peter Hinterdorfer. "AFM-Based Force Spectroscopy Guided by Recognition Imaging: A New Mode for Mapping and Studying Interaction Sites at Low Lateral Density." Methods and Protocols 2, no. 1 (January 8, 2019): 6. http://dx.doi.org/10.3390/mps2010006.

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Ligand binding to receptors is one of the most important regulatory elements in biology as it is the initiating step in signaling pathways and cascades. Thus, precisely localizing binding sites and measuring interaction forces between cognate receptor–ligand pairs leads to new insights into the molecular recognition involved in these processes. Here we present a detailed protocol about applying a technique, which combines atomic force microscopy (AFM)-based recognition imaging and force spectroscopy for studying the interaction between (membrane) receptors and ligands on the single molecule level. This method allows for the selection of a single receptor molecule reconstituted into a supported lipid membrane at low density, with the subsequent quantification of the receptor–ligand unbinding force. Based on AFM tapping mode, a cantilever tip carrying a ligand molecule is oscillated across a membrane. Topography and recognition images of reconstituted receptors are recorded simultaneously by analyzing the downward and upward parts of the oscillation, respectively. Functional receptor molecules are selected from the recognition image with nanometer resolution before the AFM is switched to the force spectroscopy mode, using positional feedback control. The combined mode allows for dynamic force probing on different pre-selected molecules. This strategy results in higher throughput when compared with force mapping. Applied to two different receptor–ligand pairs, we validated the presented new mode.

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13

Gil, Diana, Adam G. Schrum, Balbino Alarcón, and Ed Palmer. "T cell receptor engagement by peptide–MHC ligands induces a conformational change in the CD3 complex of thymocytes." Journal of Experimental Medicine 201, no. 4 (February 21, 2005): 517–22. http://dx.doi.org/10.1084/jem.20042036.

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The T cell receptor (TCR) can recognize a variety of cognate peptide/major histocompatibility complex (pMHC) ligands and translate their affinity into distinct cellular responses. To achieve this, the nonsignaling αβ heterodimer communicates ligand recognition to the CD3 signaling subunits by an unknown mechanism. In thymocytes, we found that both positive- and negative-selecting pMHC ligands expose a cryptic epitope in the CD3 complex upon TCR engagement. This conformational change is induced in vivo and requires the expression of cognate MHC. We conclude that TCR engagement with a cognate pMHC ligand induces a conformational change in the CD3 complex of thymocytes and propose that this marks an initial event during thymic selection that signals the recognition of self-antigen.

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14

Vivat, V., D. Gofflo, T. Garcia, J.-M. Wurtz, W. Bourguet, D. Philibert, and H. Gronemeyer. "Sequences in the ligand-binding domains of the human androgen and progesterone receptors which determine their distinct ligand identities." Journal of Molecular Endocrinology 18, no. 2 (April 1997): 147–60. http://dx.doi.org/10.1677/jme.0.0180147.

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ABSTRACT The natural ligands of the progesterone (PR) and androgen (AR) receptors, progesterone and testosterone, differ only by their 17β-substitution. To identify within the AR and PR ligand-binding domains (LBDs) the sequences responsible for the differential recognition of these ligands, chimeric LBDs assembled from five homologous AR/PR 'cassettes' linked to the GAL4-DNA binding domain were constructed, and their ligand binding and transactivation characteristics were determined. Replacing the central cassette 3 of PR by that of AR generated a progesterone- and testosterone-responsive PR LBD with the AR residues 788-RHLS-791 being specifically involved in testosterone recognition, while the introduction of the C-terminal PR cassette 5 into AR conferred progestin responsiveness onto the AR LBD. These results suggest that residues within AR 788-RHLS-791 interact with the testosterone 17β-OH, while PR cassette 5 apparently contains the amino acid(s) specifically involved in the recognition of the progesterone 17β-acetyl group. However, ligand binding and transactivation by these chimeras were significantly decreased compared with those of the parental LBDs, indicating that residues located outside of these cassettes contribute to the proper positioning of the steroids in the AR and PR ligand-binding pockets (LBPs). Indeed, certain AR/PR chimeras acquired efficient ligand binding, but were unable to transactivate, indicating that the ligand was improperly bound in the chimeric LBP and could not induce the conformational changes leading to a transcriptionally competent activation function (AF-2) within the LBD. The properties of the various LBD chimeras are discussed in view of the recently solved three-dimensional structures of the retinoid X receptor α apo- and retinoic acid receptor γ holo-LBDs.

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Ginsberg, M. H., J. C. Loftus, S. D'Souza, and E. F. Plow. "Ligand binding to integrins: Common and ligand specific recognition mechanisms." Cell Differentiation and Development 32, no. 3 (December 1990): 203–13. http://dx.doi.org/10.1016/0922-3371(90)90033-s.

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16

Negi, Ajay Singh, and Ajay Kumar Sood. "Electric Field–Enhanced Sensitivity of Grafted Ligands and Receptors." Clinical Chemistry 54, no. 2 (February 1, 2008): 366–70. http://dx.doi.org/10.1373/clinchem.2007.094417.

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Abstract Background: Particle-based agglutination tests consisting of receptors grafted to colloidal microparticles are useful for detecting small quantities of corresponding ligands of interest in fluid test samples, but detection limits of such tests are limited to a certain concentration and it is most desirable to lower the detection limits and to enhance the rate of recognition of ligands. Methods: A mixture of receptor-coated colloidal microparticles and corresponding ligand was sandwiched between 2 indium tin oxide–coated glass plates. Electrohydrodynamic drag from an alternating-current electric field applied perpendicular to the plates increased the local concentration of the colloidal particles, improving the chances of ligand-receptor interaction and leading to the aggregation of the colloidal particles. Results: With this technique the sensitivity of the ligand-receptor recognition was increased by a factor as large as 50. Conclusions: This method can improve the sensitivity of particle-based agglutination tests used in immunoassays and many other applications such as immunoprecipitation and chemical sniffing.

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17

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.

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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.

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18

MATSUI, Masakazu. "Ligand design for ion size recognition." Bunseki kagaku 45, no. 3 (1996): 209–23. http://dx.doi.org/10.2116/bunsekikagaku.45.209.

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19

Suehiro, Kazuhisa, Jeffrey W. Smith, and Edward F. Plow. "The Ligand Recognition Specificity of Integrins." Journal of Biological Chemistry 271, no. 17 (April 26, 1996): 10365–71. http://dx.doi.org/10.1074/jbc.271.17.10365.

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20

Suehiro, Kazuhisa, and Edward F. Plow. "Ligand Recognition by .BETA.3 Integrins." Keio Journal of Medicine 46, no. 3 (1997): 111–14. http://dx.doi.org/10.2302/kjm.46.111.

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21

Mulhbacher, Jérôme, and Daniel A. Lafontaine. "Ligand recognition determinants of guanine riboswitches." Nucleic Acids Research 35, no. 16 (August 2007): 5568–80. http://dx.doi.org/10.1093/nar/gkm572.

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22

Springer, Barry A., Stephen G. Sligar, John S. Olson, and George N. Jr Phillips. "Mechanisms of Ligand Recognition in Myoglobin." Chemical Reviews 94, no. 3 (May 1994): 699–714. http://dx.doi.org/10.1021/cr00027a007.

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23

Stephanos, Joseph J., Scott A. Farina, and Anthony W. Addison. "Iron ligand recognition by monomeric hemoglobins." Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology 1295, no. 2 (July 1996): 209–21. http://dx.doi.org/10.1016/0167-4838(96)00041-6.

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24

Yuan, Xiaojing, and Yechun Xu. "Recent Trends and Applications of Molecular Modeling in GPCR–Ligand Recognition and Structure-Based Drug Design." International Journal of Molecular Sciences 19, no. 7 (July 20, 2018): 2105. http://dx.doi.org/10.3390/ijms19072105.

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G protein-coupled receptors represent the largest family of human membrane proteins and are modulated by a variety of drugs and endogenous ligands. Molecular modeling techniques, especially enhanced sampling methods, have provided significant insight into the mechanism of GPCR–ligand recognition. Notably, the crucial role of the membrane in the ligand-receptor association process has earned much attention. Additionally, docking, together with more accurate free energy calculation methods, is playing an important role in the design of novel compounds targeting GPCRs. Here, we summarize the recent progress in the computational studies focusing on the above issues. In the future, with continuous improvement in both computational hardware and algorithms, molecular modeling would serve as an indispensable tool in a wider scope of the research concerning GPCR–ligand recognition as well as drug design targeting GPCRs.

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25

Kaur, Punit, Pradeep Sharma, Shavait Yamini, Divya Dube, Nisha Pandey, Mau Sinha, Sujata Sharma, and Tej P. Singh. "Molecular Basis of Ligand Recognition by Mammalian Peptidoglycan Recognition Protein." Biophysical Journal 104, no. 2 (January 2013): 547a. http://dx.doi.org/10.1016/j.bpj.2012.11.3034.

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Cao, Ruyin, Alejandro Giorgetti, Andreas Bauer, Bernd Neumaier, Giulia Rossetti, and Paolo Carloni. "Role of Extracellular Loops and Membrane Lipids for Ligand Recognition in the Neuronal Adenosine Receptor Type 2A: An Enhanced Sampling Simulation Study." Molecules 23, no. 10 (October 12, 2018): 2616. http://dx.doi.org/10.3390/molecules23102616.

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Human G-protein coupled receptors (GPCRs) are important targets for pharmaceutical intervention against neurological diseases. Here, we use molecular simulation to investigate the key step in ligand recognition governed by the extracellular domains in the neuronal adenosine receptor type 2A (hA2AR), a target for neuroprotective compounds. The ligand is the high-affinity antagonist (4-(2-(7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-ylamino)ethyl)phenol), embedded in a neuronal membrane mimic environment. Free energy calculations, based on well-tempered metadynamics, reproduce the experimentally measured binding affinity. The results are consistent with the available mutagenesis studies. The calculations identify a vestibular binding site, where lipids molecules can actively participate to stabilize ligand binding. Bioinformatic analyses suggest that such vestibular binding site and, in particular, the second extracellular loop, might drive the ligand toward the orthosteric binding pocket, possibly by allosteric modulation. Taken together, these findings point to a fundamental role of the interaction between extracellular loops and membrane lipids for ligands’ molecular recognition and ligand design in hA2AR.

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Takagi, J. "Structural basis for ligand recognition by RGD (Arg-Gly-Asp)-dependent integrins." Biochemical Society Transactions 32, no. 3 (June 1, 2004): 403–6. http://dx.doi.org/10.1042/bst0320403.

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Since the discovery of the RGD sequence motif as the essential cell attachment site in Fn (fibronectin), RGD-dependent ligand recognition by integrins has been the major focus of many integrin researches. Although many integrins recognize RGD-containing ligands, it is believed that residues outside the RGD motif provide specificity as well as high affinity for each integrin–ligand pair. These ‘secondary’ sites are generally assumed to interact directly with the α subunit of integrin, whereas the RGD motif binds primarily to the β subunit. This necessitates that the integrin–ligand interface comprises a relatively large, or even scattered, area. Molecular electron microscopy and single-particle analysis were performed on a headpiece fragment of integrin α5β1 in the presence and absence of bound ligand (Fn fragment), and revealed a marked shape change of the β subunit hybrid and I-like domains that is linked with the ligand docking. Furthermore, electron microscopy images revealed a focal rather than a large contact area at the α5β1–Fn interface, raising a question about ‘2-site docking model’. Kinetic analysis of real-time binding data showed that the synergy site greatly enhances kon but has little effect on the stability or koff of the complex, suggesting that the synergy site exerts its positive effect on α5β1 binding by facilitating the initial encounter, rather than by contributing to the protein–protein interaction surface. Thus the ligand recognition mechanism by integrins needs further refinement through more structural analyses of the complexes as well as kinetic analysis of binding data.

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Andersen-Nissen, Erica, Kelly D. Smith, Richard Bonneau, Roland K. Strong, and Alan Aderem. "A conserved surface on Toll-like receptor 5 recognizes bacterial flagellin." Journal of Experimental Medicine 204, no. 2 (February 5, 2007): 393–403. http://dx.doi.org/10.1084/jem.20061400.

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The molecular basis for Toll-like receptor (TLR) recognition of microbial ligands is unknown. We demonstrate that mouse and human TLR5 discriminate between different flagellins, and we use this difference to map the flagellin recognition site on TLR5 to 228 amino acids of the extracellular domain. Through molecular modeling of the TLR5 ectodomain, we identify two conserved surface-exposed regions. Mutagenesis studies demonstrate that naturally occurring amino acid variation in TLR5 residue 268 is responsible for human and mouse discrimination between flagellin molecules. Mutations within one conserved surface identify residues D295 and D367 as important for flagellin recognition. These studies localize flagellin recognition to a conserved surface on the modeled TLR5 structure, providing detailed analysis of the interaction of a TLR with its ligand. These findings suggest that ligand binding at the β sheets results in TLR activation and provide a new framework for understanding TLR–agonist interactions.

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Li, Chaoqun, Xiaojia Zhao, Xiaomin Zhu, Pengtao Xie, and Guangju Chen. "Structural Studies of the 3′,3′-cGAMP Riboswitch Induced by Cognate and Noncognate Ligands Using Molecular Dynamics Simulation." International Journal of Molecular Sciences 19, no. 11 (November 9, 2018): 3527. http://dx.doi.org/10.3390/ijms19113527.

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Riboswtich RNAs can control gene expression through the structural change induced by the corresponding small-molecule ligands. Molecular dynamics simulations and free energy calculations on the aptamer domain of the 3′,3′-cGAMP riboswitch in the ligand-free, cognate-bound and noncognate-bound states were performed to investigate the structural features of the 3′,3′-cGAMP riboswitch induced by the 3′,3′-cGAMP ligand and the specificity of ligand recognition. The results revealed that the aptamer of the 3′,3′-cGAMP riboswitch in the ligand-free state has a smaller binding pocket and a relatively compact structure versus that in the 3′,3′-cGAMP-bound state. The binding of the 3′,3′-cGAMP molecule to the 3′,3′-cGAMP riboswitch induces the rotation of P1 helix through the allosteric communication from the binding sites pocket containing the J1/2, J1/3 and J2/3 junction to the P1 helix. Simultaneously, these simulations also revealed that the preferential binding of the 3′,3′-cGAMP riboswitch to its cognate ligand, 3′,3′-cGAMP, over its noncognate ligand, c-di-GMP and c-di-AMP. The J1/2 junction in the 3′,3′-cGAMP riboswitch contributing to the specificity of ligand recognition have also been found.

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Wu, Yiran, Liting Zeng, and Suwen Zhao. "Ligands of Adrenergic Receptors: A Structural Point of View." Biomolecules 11, no. 7 (June 24, 2021): 936. http://dx.doi.org/10.3390/biom11070936.

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Adrenergic receptors are G protein-coupled receptors for epinephrine and norepinephrine. They are targets of many drugs for various conditions, including treatment of hypertension, hypotension, and asthma. Adrenergic receptors are intensively studied in structural biology, displayed for binding poses of different types of ligands. Here, we summarized molecular mechanisms of ligand recognition and receptor activation exhibited by structure. We also reviewed recent advances in structure-based ligand discovery against adrenergic receptors.

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Masson, Thibaut, Corinne Landras Guetta, Eugénie Laigre, Anne Cucchiarini, Patricia Duchambon, Marie-Paule Teulade-Fichou, and Daniela Verga. "BrdU immuno-tagged G-quadruplex ligands: a new ligand-guided immunofluorescence approach for tracking G-quadruplexes in cells." Nucleic Acids Research 49, no. 22 (December 7, 2021): 12644–60. http://dx.doi.org/10.1093/nar/gkab1166.

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Abstract G-quadruplexes (G4s) are secondary structures forming in G-rich nucleic acids. G4s are assumed to play critical roles in biology, nonetheless their detection in cells is still challenging. For tracking G4s, synthetic molecules (G4 ligands) can be used as reporters and have found wide application for this purpose through chemical functionalization with a fluorescent tag. However, this approach is limited by a low-labeling degree impeding precise visualization in specific subcellular regions. Herein, we present a new visualization strategy based on the immuno-recognition of 5-bromo-2′-deoxyuridine (5-BrdU) modified G4 ligands, functionalized prior- or post-G4-target binding by CuAAC. Remarkably, recognition of the tag by antibodies leads to the detection of the modified ligands exclusively when bound to a G4 target both in vitro, as shown by ELISA, and in cells, thereby providing a highly efficient G4-ligand Guided Immunofluorescence Staining (G4-GIS) approach. The obtained signal amplification revealed well-defined fluorescent foci located in the perinuclear space and RNase treatment revealed the preferential binding to G4-RNA. Furthermore, ligand treatment affected significantly BG4 foci formation in cells. Our work headed to the development of a new imaging approach combining the advantages of immunostaining and G4-recognition by G4 ligands leading to visualization of G4/ligands species in cells with unrivaled precision and sensitivity.

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Tateing, Suriya, and Nuttee Suree. "Decoding molecular recognition of inhibitors targeting HDAC2 via molecular dynamics simulations and configurational entropy estimation." PLOS ONE 17, no. 8 (August 18, 2022): e0273265. http://dx.doi.org/10.1371/journal.pone.0273265.

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Molecular recognition by enzymes is a complicated process involving thermodynamic energies governing protein-ligand interactions. In order to aid the estimation of inhibitory activity of compounds targeting an enzyme, several computational methods can be employed to dissect this intermolecular contact. Herein, we report a structural dynamics investigation of an epigenetic enzyme HDAC2 in differentiating its binding to various inhibitors within the sub-sites of its active site. Molecular dynamics (MD) simulation was employed to elucidate the intermolecular interactions as well as the dynamics behavior of ligand binding. MD trajectories of five distinct HDAC2-inhibitor complexes reveal that compounds lacking adequate contacts with the opening rim of the active site possess high fluctuation along the cap portion, thus weakening the overall affinity. Key intermolecular interactions determining the effective binding of inhibitors include hydrogen bonds with Gly154, Asp181, and Tyr308; hydrophobic interactions between Phe155/Phe210 and the linker region; and a pi-stacking with Arg39 at the foot pocket. Decomposition of the binding free energy calculated per-residue by MM/PBSA also indicates that the interactions within the internal foot pocket, especially with residues Met35, Leu144, Gly305, and Gly306, can contribute significantly to the ligand binding. Additionally, configurational entropy of the binding was estimated and compared to the scale of the binding free energy in order to assess its contribution to the binding and to differentiate various ligand partners. It was found that the levels of entropic contribution are comparable among a set of structurally similar carbamide ligands, while it is greatly different for the set of unrelated ligands, ranging from 2.75 to 16.38 kcal/mol for the five inhibitors examined. These findings exemplify the importance of assessing molecular dynamics as well as estimating the entropic contribution in evaluating the ligand binding mechanism.

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HOWL, John, and Mark WHEATLEY. "Molecular recognition of peptide and non-peptide ligands by the extracellular domains of neurohypophysial hormone receptors." Biochemical Journal 317, no. 2 (July 15, 1996): 577–82. http://dx.doi.org/10.1042/bj3170577.

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This study was designed to ascertain whether the extracellular loops of vasopressin/oxytocin receptors bind ligands and, if so, to locate the molecular determinants of this ligand–receptor interaction. Ligand-binding studies were employed using a rat liver V1a vasopressin receptor preparation and both peptide and non-peptide receptor ligands. Synthetic peptides corresponding to defined regions of the extracellular surface of the neurohypophysial hormone receptors recognized radioligands. These receptor mimetics inhibited the binding of radioligands to the V1a receptor with apparent affinities (pKi) ranging from 3.1 to 6.75. The same mimetics had no effect on the binding of angiotensin II to the rat AT1 receptor, indicating specificity for V1a receptor ligands. A mimetic peptide (DITYRFRGPDWL) of the first extracellular loop (ECII) of the V1a vasopressin receptor also inhibited vasopressin-stimulated, but not angiotensin II-stimulated, glycogen phosphorylase in isolated rat hepatocytes. In contrast, scrambled ECII mimetics displayed greatly reduced affinity for vasopressin. In addition, the role of peptide side-chain versus main-chain atoms in the binding of ligands by vasopressin receptors was addressed using retro–inverso peptide mimetics. Our findings indicate a precise orientation of the extracellular receptor surface (particularly the ECII domain) which facilitates the initial ‘capture’ of both peptide and non-peptide ligands. Moreover, the data indicate that the main-chain atoms of both a major binding-site determinant in the first extracellular loop of the receptor and the neurohypophysial hormones contribute significantly to the ligand–receptor interaction. These findings also suggest that soluble receptor-binding domains have therapeutic potential.

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Guzelj, Samo, Tihomir Tomašič, and Žiga Jakopin. "Novel Scaffolds for Modulation of NOD2 Identified by Pharmacophore-Based Virtual Screening." Biomolecules 12, no. 8 (July 29, 2022): 1054. http://dx.doi.org/10.3390/biom12081054.

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Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) is an innate immune pattern recognition receptor responsible for the recognition of bacterial peptidoglycan fragments. Given its central role in the formation of innate and adaptive immune responses, NOD2 represents a valuable target for modulation with agonists and antagonists. A major challenge in the discovery of novel small-molecule NOD2 modulators is the lack of a co-crystallized complex with a ligand, which has limited previous progress to ligand-based design approaches and high-throughput screening campaigns. To that end, a hybrid docking and pharmacophore modeling approach was used to identify key interactions between NOD2 ligands and residues in the putative ligand-binding site. Following docking of previously reported NOD2 ligands to a homology model of human NOD2, a structure-based pharmacophore model was created and used to virtually screen a library of commercially available compounds. Two compounds, 1 and 3, identified as hits by the pharmacophore model, exhibited NOD2 antagonist activity and are the first small-molecule NOD2 modulators identified by virtual screening to date. The newly identified NOD2 antagonist scaffolds represent valuable starting points for further optimization.

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Byzova, Tatiana V., and Edward F. Plow. "Activation of αVβ3 on Vascular Cells Controls Recognition of Prothrombin." Journal of Cell Biology 143, no. 7 (December 28, 1998): 2081–92. http://dx.doi.org/10.1083/jcb.143.7.2081.

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Regulation of vascular homeostasis depends upon collaboration between cells of the vessel wall and blood coagulation system. A direct interaction between integrin αVβ3 on endothelial cells and smooth muscle cells and prothrombin, the pivotal proenzyme of the blood coagulation system, is demonstrated and activation of the integrin is required for receptor engagement. Evidence that prothrombin is a ligand for αVβ3 on these cells include: (a) prothrombin binds to purified αVβ3 via a RGD recognition specificity; (b) prothrombin supports αVβ3-mediated adhesion of stimulated endothelial cells and smooth muscle cells; and (c) endothelial cells, either in suspension and in a monolayer, recognize soluble prothrombin via αVβ3. αVβ3-mediated cell adhesion to prothrombin, but not to fibrinogen, required activation of the receptor. Thus, the functionality of the αVβ3 receptor is ligand defined, and prothrombin and fibrinogen represent activation- dependent and activation-independent ligands. Activation of αVβ3 could be induced not only by model agonists, PMA and Mn2+, but also by a physiologically relevant agonist, ADP. Inhibition of protein kinase C and calpain prevented activation of αVβ3 on vascular cells, suggesting that these molecules are involved in the inside-out signaling events that activate the integrin. The capacity of αVβ3 to interact with prothrombin may play a significant role in the maintenance of hemostasis; and, at a general level, ligand selection by αVβ3 may be controlled by the activation state of this integrin.

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Robertson, Michael J., Justin G. Meyerowitz, Ouliana Panova, Kenneth Borrelli, and Georgios Skiniotis. "Plasticity in ligand recognition at somatostatin receptors." Nature Structural & Molecular Biology 29, no. 3 (February 24, 2022): 210–17. http://dx.doi.org/10.1038/s41594-022-00727-5.

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Ishiguro, M. "ligand Recognition and Structural Change of GPCR." Seibutsu Butsuri 41, supplement (2001): S20. http://dx.doi.org/10.2142/biophys.41.s20_3.

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CIERNIEWSKI, Czeslaw S., and Jolanta NIEWIAROWSKA. "Ligand Recognition by Cytoadhesins in Vascular Biology." Journal of Clinical Biochemistry and Nutrition 28, no. 3 (2000): 201–15. http://dx.doi.org/10.3164/jcbn.28.201.

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39

Verdino, P., C. Aldag, D. Hilvert, and I. A. Wilson. "Antibodies: specificity and promiscuity of ligand recognition." Acta Crystallographica Section A Foundations of Crystallography 62, a1 (August 6, 2006): s38. http://dx.doi.org/10.1107/s0108767306099247.

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40

Schmidt, Hayden R., Robin M. Betz, Ron O. Dror, and Andrew C. Kruse. "Structural basis for σ1 receptor ligand recognition." Nature Structural & Molecular Biology 25, no. 10 (October 2018): 981–87. http://dx.doi.org/10.1038/s41594-018-0137-2.

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41

Choi, Mihwa, Keiko Yamamoto, Hiroyuki Masuno, Kinichi Nakashima, Tetsuya Taga, and Sachiko Yamada. "Ligand recognition by the vitamin D receptor." Bioorganic & Medicinal Chemistry 9, no. 7 (July 2001): 1721–30. http://dx.doi.org/10.1016/s0968-0896(01)00060-8.

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42

Takagi, Junichi. "Structural basis for ligand recognition by integrins." Current Opinion in Cell Biology 19, no. 5 (October 2007): 557–64. http://dx.doi.org/10.1016/j.ceb.2007.09.002.

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43

Riccardi, Laura, Luca Gabrielli, Xiaohuan Sun, Federico De Biasi, Federico Rastrelli, Fabrizio Mancin, and Marco De Vivo. "Nanoparticle-Based Receptors Mimic Protein-Ligand Recognition." Chem 3, no. 1 (July 2017): 92–109. http://dx.doi.org/10.1016/j.chempr.2017.05.016.

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Kanlikilicer, Pinar, Nilay Budeyri, Berna Sariyar Akbulut, Amable Hortacsu, and Elif Ozkirimli. "Dynamic Analysis of Beta-lactamase Ligand Recognition." Biophysical Journal 96, no. 3 (February 2009): 443a. http://dx.doi.org/10.1016/j.bpj.2008.12.2274.

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Davis, Mark M., J. Jay Boniface, Ziv Reich, Daniel Lyons, Johannes Hampl, Bernhard Arden, and Yueh-hsiu Chien. "LIGAND RECOGNITION BY αβ T CELL RECEPTORS." Annual Review of Immunology 16, no. 1 (April 1998): 523–44. http://dx.doi.org/10.1146/annurev.immunol.16.1.523.

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Smith, Richard D., Liegi Hu, Jayson A. Falkner, Mark L. Benson, Jason P. Nerothin, and Heather A. Carlson. "Exploring protein–ligand recognition with Binding MOAD." Journal of Molecular Graphics and Modelling 24, no. 6 (May 2006): 414–25. http://dx.doi.org/10.1016/j.jmgm.2005.08.002.

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Heiring, Christoph, Björn Dahlbäck, and Yves A. Muller. "Ligand Recognition and Homophilic Interactions in Tyro3." Journal of Biological Chemistry 279, no. 8 (November 17, 2003): 6952–58. http://dx.doi.org/10.1074/jbc.m311750200.

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Sun, Shuguang, and Kathryn Thomasson. "Molecular recognition of a tris(histidine) ligand." Chemical Communications, no. 4 (1998): 519–20. http://dx.doi.org/10.1039/a706711i.

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Brodsky, Igor, and Ruslan Medzhitov. "Two Modes of Ligand Recognition by TLRs." Cell 130, no. 6 (September 2007): 979–81. http://dx.doi.org/10.1016/j.cell.2007.09.009.

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Kéry, Vladimír, Jiři J. F. Křepinský, Christopher D. Warren, Peter Capek, and Philip D. Stahl. "Ligand recognition by purified human mannose receptor." Archives of Biochemistry and Biophysics 298, no. 1 (October 1992): 49–55. http://dx.doi.org/10.1016/0003-9861(92)90092-b.

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