Locating ligand binding sites in G-protein coupled receptors using combined information from docking and sequence conservation

PeerJ

article

Ashley Ryan Vidad¹  Stephen Macaspac¹  Ho Leung Ng² 

[1] Department of Chemistry, University of Hawaii at Manoa;Department of Biochemistry and Molecular Biophysics, Kansas State University

关键词: Ligand binding sites;    GPCR;    GPER;    Drug binding sites;    Bioinformatics;    Modeling;    Docking;    Structure conservation;    Molecular evolution;   

DOI  :  10.7717/peerj.12219

学科分类：社会科学、人文和艺术（综合）

来源: Inra

【 摘 要 】

GPCRs (G-protein coupled receptors) are the largest family of drug targets and share a conserved structure. Binding sites are unknown for many important GPCR ligands due to the difficulties of GPCR recombinant expression, biochemistry, and crystallography. We describe our approach, ConDockSite, for predicting ligand binding sites in class A GPCRs using combined information from surface conservation and docking, starting from crystal structures or homology models. We demonstrate the effectiveness of ConDockSite on crystallized class A GPCRs such as the beta2 adrenergic and A2A adenosine receptors. We also demonstrate that ConDockSite successfully predicts ligand binding sites from high-quality homology models. Finally, we apply ConDockSite to predict the ligand binding sites on a structurally uncharacterized GPCR, GPER, the G-protein coupled estrogen receptor. Most of the sites predicted by ConDockSite match those found in other independent modeling studies. ConDockSite predicts that four ligands bind to a common location on GPER at a site deep in the receptor cleft. Incorporating sequence conservation information in ConDockSite overcomes errors introduced from physics-based scoring functions and homology modeling.

【 授权许可】

CC BY