Exploring the Activation Mechanism of a Metabotropic Glutamate Receptor Homodimer via Molecular Dynamics Simulation.

Abstract

Metabotropic glutamate receptors of class C GPCRs exist as constitutive dimers, which play important roles in activating excitatory synapses of the central nerve system. However, the activation mechanism induced by agonists has not been clarified on experiments. To address the problem, we used microsecond all-atom molecular dynamics (MD) simulation couple with protein structure network (PSN) to explore the glutamate-induced activation for the mGluR1 homodimer. The results indicate that the glutamate binding stabilizes not only the closure of venus flytrap domains but also the polar interaction of LB2-LB2, in turn keeping the extracelluar domain in the active state. The activation of the excelluar domain drives transmembrane domains (TMDs) of the two protomers closer and induces aymmetric activation for the TMD domains of the two protomers. One protomer with lower binding affinity to the agonist is activated while the other protomer with higher binding energy is still in the inactive state. The PSN analysis identifies the allostrical regulation-pathway from the ligand-binding pocket in the extracellur domain to the G-protein binding site in the intracellur TMD region, and further reveals that the asymmetric activation is attributed to be a combination of trans-pathway and cis-pathway regulations from the two glumatates, rather than a single activation pathway. These observations could provide valuable molecular information for understanding of the structure and the implication in drug efficacy for the class C GPCR dimers.