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

ABSTRACT: Signaling bias is the propensity for some agonists to preferentially stimulate G protein-coupled receptor (GPCR) signaling through one intracellular pathway versus another. We previously identified a G protein-biased agonist of the D₂ dopamine receptor (D2R) that results in impaired β-arrestin recruitment. This signaling bias was predicted to arise from unique interactions of the ligand with a hydrophobic pocket at the interface of the second extracellular loop and fifth transmembrane segment of the D2R. Here, we showed that residue Phe189 within this pocket (position 5.38 using Ballesteros-Weinstein numbering) functions as a microswitch for regulating receptor interactions with β-arrestin. This residue is relatively conserved among class A GPCRs, and analogous mutations within

SUBMITTER: Sanchez-Soto M 

PROVIDER: S-EPMC7236428 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature