Deciphering the GPER/GPR30-agonist and antagonists interactions using molecular modeling studies, molecular dynamics, and docking simulations

Abstract

The G-protein coupled estrogen receptor 1 GPER/GPR30 is a transmembrane seven-helix (7TM) receptor involved in the growth and proliferation of breast cancer. Due to the absence of a crystal structure of GPER/GPR30, in this work, molecular modeling studies have been carried out to build a three-dimensional structure, which was subsequently refined by molecular dynamics (MD) simulations (up to 120 ns). Furthermore, we explored GPER/GPR30's molecular recognition properties by using reported agonist ligands (G1, estradiol (E2), tamoxifen, and fulvestrant) and the antagonist ligands (G15 and G36) in subsequent docking studies. Our results identified the E2 binding site on GPER/GPR30, as well as other receptor cavities for accepting large volume ligands, through GPER/GPR30 π-π, hydrophobic, and hydrogen bond interactions. Snapshots of the MD trajectory at 14 and 70 ns showed almost identical binding motifs for G1 and G15. It was also observed that C107 interacts with the acetyl oxygen of G1 (at 14 ns) and that at 70 ns the residue E275 interacts with the acetyl group and with the oxygen from the other agonist whereas the isopropyl group of G36 is oriented toward Met141, suggesting that both C107 and E275 could be involved in the protein activation. This contribution suggest that GPER1 has great structural changes which explain its great capacity to accept diverse ligands, and also, the same ligand could be recognized in different binding pose according to GPER structural conformations.

The effects of (−)-epicatechin on endothelial cells involve the G protein-coupled estrogen receptor (GPER)

“…We used as a target the tridimensional (3-D) model of GPER previously developed, refined by molecular dynamics (MD) simulations and validated by docking studies (21). This 3-D model of GPER was built using the GPCR I-Tasser web site (22) (a specialized server for building 3-D models of GPCRs).…”

“…The NAMD 2.9 program was used to perform the GPER refinement by MD simulations. The 14 and 70 ns snapshots derived from MD were used for docking studies, as these snapshots appeared to evidenced key molecular recognitions of G1 (agonist) and G15 (antagonist) in the binding site of GPER (21). …”

“…Docking studies were performed as previously described (21), with slight modifications. Docking parameters employed here consisted on a grid box of 60 X 60 X 60 Å 3 centered at the Cα of F208, as this residue has been suggested by us and others (23) to be the protein active site centre, other parameters were kept the same.…”

Macromolecular Modelling and Docking Simulations for the Discovery of Selective GPER Ligands

“…Certain models of GPER were obtained by a web server for 3D-structure prediction such as I-TASSER and then refined by extensive MD simulations (22,23); in addition, virtual and biomolecular screening taking advantage of models deposited in appropriate data banks were employed as well. Using the aforementioned approaches, several different natural and synthetic ligands of GPER (Fig.…”

The nonsteroidal mycoestrogen zearalenone and its five metabolites suppress LH secretion from the bovine anterior pituitary cells via the estradiol receptor GPR30 in vitro

“…We used G36, a GPR30 antagonist that was recently 79 developed for human cancer research [22][23][24] and is known to bind to receptors on bovine 80 satellite cells [25], to test the hypothesis that GPR30 bound with ZEN or one of the five ZEN 81 metabolites suppresses GnRH-induced LH secretion from the bovine AP cells in vitro. Institute Inc., Osaka, Japan) dissolved in DMEM to stimulate LH secretion.…”