Research ArticleGPCR SIGNALING

A structural basis for how ligand binding site changes can allosterically regulate GPCR signaling and engender functional selectivity

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Science Signaling  04 Feb 2020:
Vol. 13, Issue 617, eaaw5885
DOI: 10.1126/scisignal.aaw5885

A biasing position for GPCRs

GPCRs are the largest class of druggable receptors in the human proteome. Drugs that preferentially activate G protein– or β-arrestin–dependent signaling downstream of GPCRs are less likely to come with unwanted side effects. Using biochemical analyses, Sanchez-Soto et al. identified a specific conserved residue in the ligand binding site for multiple GPCRs that modulate β-arrestin–dependent signaling while minimally affecting that mediated by G proteins. Molecular dynamics simulations showed that mutations in this residue resulted in conformational changes that were expected to allosterically affect the interaction of the receptor with β-arrestin. These findings describe a mechanism by which changes in the ligand binding site of GPCRs can result in biased downstream signaling.

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