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Comparison analysis of primary ligand-binding sites in seven-helix membrane proteins.

ABSTRACT: Seven-helix transmembrane proteins, including the G-protein-coupled receptors (GPCRs), mediate a broad range of fundamental cellular activities through binding to a wide range of ligands. Understanding the structural basis for the ligand-binding selectivity of these proteins is of significance to their structure-based drug design. Comparison analysis of proteins' ligand-binding sites provides a useful way to study their structure-activity relationships. Various computational methods have been developed for the binding-site comparison of soluble proteins. In this work, we applied this approach to the analysis of the primary ligand-binding sites of 92 seven-helix transmembrane proteins. Results of the studies confirmed that the binding site of bacterial rhodopsins is indeed different from all GPCRs. In the latter group, further comparison of the binding sites indicated a group of residues that could be responsible for ligand-binding selectivity and important for structure-based drug design. Furthermore, unexpected binding-site dissimilarities were observed among adrenergic and adenosine receptors, suggesting that the percentage of the overall sequence identity between a target protein and a template protein alone is not sufficient for selecting the best template for homology modeling of seven-helix membrane proteins. These results provided novel insight into the structural basis of ligand-binding selectivity of seven-helix membrane proteins and are of practical use to the computational modeling of these proteins.

SUBMITTER: Pabuwal V

PROVIDER: S-EPMC2966529 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Comparison analysis of primary ligand-binding sites in seven-helix membrane proteins.

Pabuwal Vagmita V Li Zhijun Z

Biopolymers 20110101 1

Seven-helix transmembrane proteins, including the G-protein-coupled receptors (GPCRs), mediate a broad range of fundamental cellular activities through binding to a wide range of ligands. Understanding the structural basis for the ligand-binding selectivity of these proteins is of significance to their structure-based drug design. Comparison analysis of proteins' ligand-binding sites provides a useful way to study their structure-activity relationships. Various computational methods have been de ...[more]

PMID: 20672377

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Project description:BackgroundMany integral membrane proteins, like their non-membrane counterparts, form either transient or permanent multi-subunit complexes in order to carry out their biochemical function. Computational methods that provide structural details of these interactions are needed since, despite their importance, relatively few structures of membrane protein complexes are available.ResultsWe present a method for predicting which residues are in protein-protein binding sites within the transmembrane regions of membrane proteins. The method uses a Random Forest classifier trained on residue type distributions and evolutionary conservation for individual surface residues, followed by spatial averaging of the residue scores. The prediction accuracy achieved for membrane proteins is comparable to that for non-membrane proteins. Also, like previous results for non-membrane proteins, the accuracy is significantly higher for residues distant from the binding site boundary. Furthermore, a predictor trained on non-membrane proteins was found to yield poor accuracy on membrane proteins, as expected from the different distribution of surface residue types between the two classes of proteins. Thus, although the same procedure can be used to predict binding sites in membrane and non-membrane proteins, separate predictors trained on each class of proteins are required. Finally, the contribution of each residue property to the overall prediction accuracy is analyzed and prediction examples are discussed.ConclusionGiven a membrane protein structure and a multiple alignment of related sequences, the presented method gives a prioritized list of which surface residues participate in intramembrane protein-protein interactions. The method has potential applications in guiding the experimental verification of membrane protein interactions, structure-based drug discovery, and also in constraining the search space for computational methods, such as protein docking or threading, that predict membrane protein complex structures.

Dataset Information

Comparison analysis of primary ligand-binding sites in seven-helix membrane proteins.

Publications

Comparison analysis of primary ligand-binding sites in seven-helix membrane proteins.

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