Exploring the Binding Site of the G Protein-Coupled Receptor GPR119 Model using a Pair of Diastereomers with Opposing Action

Abstract

GPR119 is a Class A (rhodopsin-like) G-protein coupled receptor that has insulin-regulating activity. GPR119 agonists stimulate glucose-dependent insulin secretion in vitro and lower elevated blood glucose in vivo. Hence, the GPR119 receptor has emerged as an important target for the treatment of type 2 diabetes. An initial GPR119 homology model was constructed using the adenosine A2A receptor crystal structure bound to an antagonist at 2.6A resolution (PDB id: 3EML) as the template. The preliminary model was refined by exploring the flexibility of individual helices using the Monte Carlo/simulated annealing method, Conformational Memories (CM). CM employs multiple Monte Carlo/simulated annealing random walks, exploring peptide and protein dihedral conformational space. A pair of previously reported diastereomers, one of which acts as a GPR119 receptor agonist and the other as an antagonist, were docked into the active (R∗) and inactive (R) receptor models. The putative binding site of the preliminary R model starts between the top of transmembrane helices (TMHs) 2 and 7 and spans the bundle in a shallow diagonal direction, almost perpendicular to the TMH region. The floor of the binding site is between TMHs 3, 5 and 6 at the level of F234(6.44) (middle of the TMH bundle). W238(6.48) (χ1 = g+) places its bulk between TMHs 6 and 7. The only charged amino acid that is accessible to the binding site, R81(3.28), was used as the primary interaction site for both compounds. The GPR119 R∗ state binding site is more vertical compared to the R state and somewhat deeper because of a χ1 rotamer change of W238(6.48) to a trans conformation in the R∗ state, which places its bulk between TMHs 5 and 6.