title: 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.
authors.affiliation: a Laboratorio de modelado Molecular y Diseño de Fármacos (Laboratory of Molecular Modeling and Drug Design), Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina , Instituto Politécnico Nacional , Plan de San Luis y Díaz Mirón, 11340 México, D.F. , Mexico.
authors.forename: D
authors.initials: D
authors.lastname: Méndez-Luna
authors.forename: M
authors.initials: M
authors.lastname: Martínez-Archundia
authors.forename: Rachid C
authors.initials: RC
authors.lastname: Maroun
authors.forename: G
authors.initials: G
authors.lastname: Ceballos-Reyes
authors.forename: M J
authors.initials: MJ
authors.lastname: Fragoso-Vázquez
authors.forename: D E
authors.initials: DE
authors.lastname: González-Juárez
authors.forename: J
authors.initials: J
authors.lastname: Correa-Basurto
mesh_terms: D020816:Amino Acid Motifs; D052117:Benzodioxoles / Q000737:chemistry*; D001665:Binding Sites; D004958:Estradiol / Q000031:analogs & derivatives* / Q000737:chemistry*; D000077267:Fulvestrant; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011804:Quinolines / Q000737:chemistry*; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000737:chemistry*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry*; D013629:Tamoxifen / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: C568862:4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-3H-cyclopenta(c)quinoline; D052117:Benzodioxoles; C000603178:G36 compound; C109584:GPER1 protein, human; D008024:Ligands; D011804:Quinolines; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D013629:Tamoxifen; D000077267:Fulvestrant; D004958:Estradiol
keywords: GPR30; GPR30 docking; ligand recognition; molecular dynamics simulations