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 well-characterized, 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.
