G-protein-coupled receptors (GPCRs) are the largest superfamily of human membrane proteins and serve as primary targets of ~1/3 of currently marketed drugs. Four subtypes of adenosine receptors, the A1, A2A, A2B, and A3, mediate a broad range of physiological functions. They have emerged as important therapeutic targets for treating cardiac ischemia, neuropathic pain and cancer. During function, the A1and A3receptors preferentially bind the Gi/oproteins, while the A2Aand A2Breceptors preferentially bind the Gsproteins. Moreover, the GPCR–G protein interactions are modulated byallosteric ligands. These ligands bind to a putative extracellular site of adenosine receptors with divergent sequences and conformations and have emerged as promising candidates as selective GPCR drugs. To date, adenosine receptors are the sole subfamily of GPCRs that have X-ray or cryo-EM structures determined in complex with distinct G proteins, i.e., the A1and A2Areceptors coupled with the Giand Gsproteins, respectively. Here, enhanced molecular dynamics simulations have been performed on the GPCR-G protein complex structures, as well as spontaneous binding of prototypical allosteric modulators to the adenosine receptors. These simulations have revealed important insights into dynamic mechanisms of the allosteric modulation of adenosine receptors and GPCR–G protein interactions.

Enhanced molecular dynamics simulations of G-protein-coupled receptor-G protein interactions

2019 Spring National Meeting

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