G Protein‐Coupled Estrogen Receptor (GPER) Agonist Dual Binding Mode Analyses Toward Understanding of Its Activation Mechanism: A Comparative Homology Modeling Approach

Abstract

G protein-coupled estrogen receptor (GPER) has been shown to be important in several disease states such as estrogen sensitive cancers. While several selective ligands have been identified for the receptor, little is known about how they interact with GPER and how their structures influence their activity. Specifically, within one series of ligands, whose structure varied only at one position, the replacement of a hydrogen atom with an acetyl group changed a potent antagonist into a potent agonist. In this study, two GPER homology models were constructed based on the x-ray crystal structures of both the active and inactive β2-adrenergic receptors (β2AR) in an effort to characterize the differences of binding modes between agonists and antagonists to the receptor, and to understand their activity in relation to their structures. The knowledge attained in this study is expected to provide valuable information on GPER ligands structure activity relationship to benefit future rational design of potent agonists and antagonists of the receptor for potential therapeutic applications.

Development of Therapeutics That Induce Mitochondrial Biogenesis for the Treatment of Acute and Chronic Degenerative Diseases

“…The GPER-selective ligand G-1( 18 ) 160 is structurally similar to 14 but is unable to form hydrogen bonds in the nuclear estrogen receptors; 160 however, 18 ’s acetyl group and pseudosymmetry allows engagement of specific residues of the GPER to stabilize the active conformation. 161–162 …”

Steroid-Functionalized Titanocenes: Docking Studies with Estrogen Receptor Alpha

“…ERβ is responsive to estrogens and it has antiproliferative and tumor growth inhibition properties on breast cancer [27][28][29]. Perhaps more important, the MCF-7 cell line also expresses G-protein coupled estrogen receptor (GPER), which is activated by estrogens and steroids [30][31][32][33]. Crosstalk between GPER and ERs has been suggested in uterine and ovarian cancers [34][35][36].…”

Computational fishing of new DNA methyltransferase inhibitors from natural products

“…A comparative structural analysis for DMNTs was performed with SYBYL-X 2.0 by multiple sequence alignments (% of identity, %ID) and spatial similarity (RMSD in Å) [58]. Details are shown in Table S2, S3 and S4.…”