title: Homology Modeling, Validation and Dynamics of the G Protein-coupled Estrogen Receptor 1 (GPER-1).
abstract: Estrogens exert their action mainly by binding three receptors, namely estrogen receptors α and β (ERα and ERβ) and GPER-1 (G-protein coupled estrogen receptor 1). While the patho-physiological role of both ERα and ERβ has been deeply investigated, the role of GPER-1 in estrogens' signaling has not been clearly defined yet. Unfortunately, only few GPER-1 selective ligands were discovered so far, and the real efficiency of such compounds is still matter of debate. To better understand the physiological relevance of GPER-1, new selective chemical probes are higly needed. In this scenario, we report herein the generation and validation of a three-dimensional (3-D) GPER-1 homology model by means of docking studies and molecular dynamics simulations. The model thus generated was employed to (i) decipher the structural basis underlying the ability of estrogens and some Selective Estrogen Receptor Modulators (SERMs) to bind GPER-1 and classical ERα and ERβ, and (ii) generate a reliable G1/GPER-1 complex useful in rationalizing the pharmacological profile of G1 reported in the literature. The G1/GPER-1 complex herein reported could be further exploited in drug design approaches aimed at improving the pharmacological profile of G1 or at identifying new chemical entities (NCEs) as potential modulators of GPER-1.
authors.affiliation: P4T Group, Dipartimento di Farmacia, Università degli Studi di Parma, Viale delle Scienze, 27/A, 43124, Parma, Italy . agostino.bruno@unipr.it.
authors.forename: Agostino
authors.initials: A
authors.lastname: Bruno
authors.affiliation: Dipartimento di Farmacia e Sienze della Salute e della Nutrizione, Università della Calabria, Edificio Polifunzionale, 87036, Arcavacata di Rende (CS, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Aiello
authors.affiliation: P4T Group, Dipartimento di Farmacia, Università degli Studi di Parma, Viale delle Scienze, 27/A, 43124, Parma, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Costantino
authors.affiliation: P4T Group, Dipartimento di Farmacia, Università degli Studi di Parma, Viale delle Scienze, 27/A, 43124, Parma, Italy . marco.radi@unipr.it.
authors.forename: Marco
authors.initials: M
authors.lastname: Radi
mesh_terms: D047628:Estrogen Receptor alpha / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011485:Protein Binding / Q000502:physiology; D011960:Receptors, Estrogen / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D020845:Selective Estrogen Receptor Modulators / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D040681:Structural Homology, Protein
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; C109584:GPER1 protein, human; D008024:Ligands; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D020845:Selective Estrogen Receptor Modulators
keywords: Estrogens; GPER-1; Homology Modelling; Molecular Dynamics Simulations