In a groundbreaking study, a multinational research team led by Dr. Adnan Sljoka (RIKEN AIP) and Prof. Akio Kitao (Tokyo Tech), in collaboration with Prof. Scott Prosser (University of Toronto), has carried out experimental and computational studies to elucidate the mechanisms behind G protein selectivity and efficacy in the human adenosine A2A receptor (A2AR). A2AR is a member of major drug targets G protein-coupled receptor (GPCR) superfamily, which engages the G protein and initiates cell signaling, influencing heart health, inflammation, cancer, and brain diseases. Scientists have made a breakthrough in understanding how A2AR can engage and activate multiple binding G-proteins and the mechanisms of this selective coupling. The research team discovered that the hallmark coupling promiscuity in A2AR is a direct consequence of changes in activation conformations. Moreover, the long-range (allosteric) communication mechanisms elegantly control the sampling of specific conformers within a dynamic conformational ensemble. This study offers profound insights into GPCRs selectivity and biased signaling. These findings are expected to have major implications in drug discovery and pave the way for novel GPCR-targeted therapeutic strategies in treating various human conditions, including cancer and neurogenerative disorders. This research will also enable the design of more generalized computational and AI-driven studies, pushing the boundaries in GPCR activation mechanisms and next-generation pharmacology.
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Tokyo Tech News
Nature Chemical Biology
