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. 2024 Nov 4;25(1):343.
doi: 10.1186/s12859-024-05962-9.

GPCR-BSD: a database of binding sites of human G-protein coupled receptors under diverse states

Affiliations

GPCR-BSD: a database of binding sites of human G-protein coupled receptors under diverse states

Fan Liu et al. BMC Bioinformatics. .

Abstract

G-protein coupled receptors (GPCRs), the largest family of membrane proteins in human body, involve a great variety of biological processes and thus have become highly valuable drug targets. By binding with ligands (e.g., drugs), GPCRs switch between active and inactive conformational states, thereby performing functions such as signal transmission. The changes in binding pockets under different states are important for a better understanding of drug-target interactions. Therefore it is critical, as well as a practical need, to obtain binding sites in human GPCR structures. We report a database (called GPCR-BSD) that collects 127,990 predicted binding sites of 803 GPCRs under active and inactive states (thus 1,606 structures in total). The binding sites were identified from the predicted GPCR structures by executing three geometric-based pocket prediction methods, fpocket, CavityPlus and GHECOM. The server provides query, visualization, and comparison of the predicted binding sites for both GPCR predicted and experimentally determined structures recorded in PDB. We evaluated the identified pockets of 132 experimentally determined human GPCR structures in terms of pocket residue coverage, pocket center distance and redocking accuracy. The evaluation showed that fpocket and CavityPlus methods performed better and successfully predicted orthosteric binding sites in over 60% of the 132 experimentally determined structures. The GPCR Binding Site database is freely accessible at https://gpcrbs.bigdata.jcmsc.cn . This study not only provides a systematic evaluation of the commonly-used fpocket and CavityPlus methods for the first time but also meets the need for binding site information in GPCR studies.

Keywords: Binding site; Database; G-protein coupled receptor; Key residue; State-specific structure.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Comparison of muscarinic acetylcholine receptor M2 receptor structure in active (PDB: 4MQT) and inactive (PDB: 5YC8) states: a shifting in TM6 backbones; b orthosteric and allosteric binding sites in the active state; c orthosteric and allosteric binding sites in the inactive state; d shifting of the orthosteric binding pocket residues and surfaces e shifting of the allosteric binding pocket surfaces, f pocket width of the allosteric binding site measured in the active state, g pocket width of the allosteric binding site measured in the inactive state
Fig. 2
Fig. 2
The flowchart of building the GPCR binding site database and evaluating the pocket prediction results
Fig. 3
Fig. 3
The GPCR Binding Site database features: a The statistics of all structures and pocket data; b 3D visualization of surfaces of predicted binding pockets; c snake plot visualization of pocket residues and docking grid parameters; d comparison of different structures; e comparison of predicted pockets in different structures
Fig. 4
Fig. 4
Comparison of predicted and actual pocket volume fold change distribution between three methods in experimentally determined structures
Fig. 5
Fig. 5
Comparison between pocket RMSD and pocket prediction results of predicted structures
Fig. 6
Fig. 6
Two representative examples of pocket prediction results: a CavityPlus prediction (cyan) on PDB 8H8J did not detect the original orthosteric binding site (yellow), b fpocket prediction (cyan) on PDB 4MQT found a large pocket region that includes both orthosteric and allosteric ligand

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