A TM7 conformational switch governs GPCR transducer selectivity
Abstract
Deciphering transducer selectivity in G protein-coupled receptors (GPCRs) is essential for developing next-generation therapeutics with improved safety profiles. Here, we identify (R)-141, a μ-opioid receptor (μOR) agonist with a distinct scaffold that exhibits exceptional G protein bias. To decode the underlying mechanism, we determined the cryo-EM structures of μOR bound to (R)-141 in complex with Gi and with GRK2. Our structural, functional and dynamics data together reveal that (R)-141 achieves this selectivity through a stepwise gating mechanism, in which the conformational dynamics of TM7 serves as a terminal checkpoint. This "conformational veto" by TM7 provides a mechanism to modulate β-arrestin recruitment at the final step. Collectively, our work provides a systemic vision of transducer selectivity and a framework for rational biased drug design.
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