Locating the ligand binding Sites for the G-protein coupled estrogen receptor (GPER) using combined information from docking and sequence conservation

Abstract

High concentrations of estrogenic compounds can overstimulate estrogen receptors and potentially lead to breast, ovarian, and cervical cancers. Recently, a G-protein coupled estrogen receptor (GPER/GPR30) was discovered that has no structural similarity to the wellcharacterized, classical estrogen receptor ERα. The crystal structure of GPER has not yet been determined, and the ligand binding sites have not yet been experimentally identified. The recent explosion of GPCR crystal structures now allow homology modeling with unprecedented reliability. We create, validate, and describe a homology model for GPER. We describe and apply ConDock, the first hybrid scoring function to use information from protein surface conservation and ligand docking, to predict binding sites on GPER for four ligands, estradiol, G1, G15, and tamoxifen. ConDock is a simple product function of sequence conservation and binding energy scores. ConDock predicts that all four ligands bind to the same location on GPER, centered on L119, H307, and N310; this site is deeper in the receptor cleft than are ligand binding sites predicted by previous studies. We compare the sites predicted by ConDock and traditional methods analyzing surface geometry, surface conservation, and ligand chemical interactions. Incorporating sequence conservation information in ConDock avoids errors resulting from physics-based scoring functions and modeling.

A novel GPER antagonist protects against the formation of estrogen-induced cholesterol gallstones in female mice

“…The selectivity studies show that CIMBA and 21 M. While CIMBA 21 displays binding to M. These results are not surprising because the molecular modeling studies on GPER and the classical ER from our group and others are in agreement that estrogenic compounds bind within a similar binding pocket as each other (33,34,(44)(45)(46)(47). Due to the proposed similarity between the binding pockets for these three receptors, it is not surprising to observe off-target 24 binding by some GPER ligands at high concentrations (16)(17)(18).…”