Construction of a GPR3 Homology Model Using Conformational Memories

Abstract

GPR3 is an orphan receptor which belongs to the Class A family of G-Protein Coupled Receptors. It shares high sequence similarity with GPR6, GPR12 (64 and 61%), the lysophospholipid receptors S1P1 and LPA1 (34 and 33%), and the cannabinoid receptors CB1 and CB2 (21 and 26%). GPR3 is predominantly expressed in mammalian brain and oocytes and it is known as a Gαs-coupled receptor activated constitutively in cells.As demonstrated by different research groups, GPR3 represents a possible target for the treatment of different pathological conditions such as Alzheimer's disease, oocyte maturation or neuropathic pain. However, the lack of potent and selective GPR3 ligands is delaying the exploitation of this promising therapeutic target. In this context, we aim to develop a homology model which helps us to elucidate the structural determinants governing ligand-receptor interactions.For that purpose, we constructed a GPR3 model based on the crystallized S1P1 receptor structure (Hanson et al, Science 2012). Sequence divergences in transmembrane helixes 1, 4, 6 and 7 have been explored using the Monte Carlo/simulated annealing program, Conformational Memories (Whitnell et al, J. Comput. Chem. 2007). Extracellular and intracellular loop geometries were calculated using Modeller v9.1. Energy minimizations of the resultant R and R∗ models were performed using the OPLS2005 all atom force field in Macromodel (Schrodinger, 2015). As in S1P1 receptor, the N-terminus of the GPR3 model displays a helical portion and short random coil region that covers the top of the binding crevice.The development of the GPR3 active and inactive state models will enable the rational design of novel GPR3 ligands which may serve as research tools for further understanding of the biological role of this orphan receptor. [Support: NIH KO5 DA021358 and NIH RO1 DA03934 (PHR)].