Abstract
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.
Highlights
GPCRs (G-protein coupled receptors) are the largest family of drug targets and the targets of >30% of all drugs
We demonstrate the effectiveness of ConDockSite for identifying ligand binding sites for the two best characterized class A GPCRs with known crystal structures, the β2 adrenergic
We developed ConDockSite to predict ligand binding pockets using information from surface conservation and docking calculations
Summary
GPCRs (G-protein coupled receptors) are the largest family of drug targets and the targets of >30% of all drugs. Because they are membrane proteins with flexible and dynamic structures, biochemical and crystallography experiments are difficult. ~87 GPCRs out of ~800 in the human genome have been crystallized despite their great pharmacological importance. GPCR homology modeling remains challenging due to conformational flexibility and the abundance of flexible loops (Lai et al, 2017). Crystal structures have shown that the large majority of ligands bind in the large central, extracellular cavity of GPCRs, but the specific binding sites in the cavity can vary widely between different. Locating ligand binding sites in G-protein coupled receptors using combined information from docking and sequence conservation.
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