Mechanistic insight into the impact of a bivalent ligand on the structure and dynamics of a GPCR oligomer.

ABSTRACT: Development of effective bivalent ligands has become the focus of intensive research toward modulation of G protein-coupled receptor (GPCR) oligomers, particularly in the field of GPCR pharmacology. Experimental studies have shown that they increased binding affinity and signaling potency compared to their monovalent counterparts, yet underlying molecular mechanism remains elusive. To address this, we performed accelerated molecular dynamics simulations on bivalent-ligand bound Adenosine 2A receptor (A_2AR) dimer in the context of a modeled tetramer, which consists of A_2AR and dopamine 2 receptor (D₂R) homodimers and their cognate G proteins. Our results demonstrate that bivalent ligand impacted interactions between pharmacophore groups and ligand binding re

SUBMITTER: Mansoor S 

PROVIDER: S-EPMC8861583 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature