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

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-dimen...

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Bibliographic Details
Published in:Journal of biomolecular structure & dynamics 2015-10, Vol.33 (10), p.2161-2172
Main Authors: Méndez-Luna, D., Martínez-Archundia, M., Maroun, Rachid C., Ceballos-Reyes, G., Fragoso-Vázquez, M.J., González-Juárez, D.E., Correa-Basurto, J.
Format: Article
Language:English
Subjects:
Amino Acid Motifs
Benzodioxoles - chemistry
Binding Sites
Estradiol - analogs & derivatives
Estradiol - chemistry
Fulvestrant
GPR30
GPR30 docking
Humans
Hydrogen Bonding
Life Sciences
ligand recognition
Ligands
Molecular Docking Simulation
Molecular Dynamics Simulation
molecular dynamics simulations
Molecular Sequence Data
Protein Binding
Protein Structure, Secondary
Protein Structure, Tertiary
Quinolines - chemistry
Receptors, Estrogen - antagonists & inhibitors
Receptors, Estrogen - chemistry
Receptors, G-Protein-Coupled - agonists
Receptors, G-Protein-Coupled - antagonists & inhibitors
Receptors, G-Protein-Coupled - chemistry
Tamoxifen - chemistry
Thermodynamics
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Summary: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.
ISSN:0739-1102
1538-0254
DOI:10.1080/07391102.2014.994102