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 ?-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 ?-arrestin. This residue is relatively conserved among class A GPCRs, and analogous mutations within other GPCRs similarly impaired ?-arrestin recruitment while maintaining G protein signaling. To investigate the mechanism of this signaling bias, we used an active-state structure of the ?2-adrenergic receptor (?2R) to build ?2R-WT and ?2R-Y1995.38A models in complex with the full ?2R agonist BI-167107 for molecular dynamics simulations. These analyses identified conformational rearrangements in ?2R-Y1995.38A that propagated from the extracellular ligand binding site to the intracellular surface, resulting in a modified orientation of the second intracellular loop in ?2R-Y1995.38A, which is predicted to affect its interactions with ?-arrestin. Our findings provide a structural basis for how ligand binding site alterations can allosterically affect GPCR-transducer interactions and result in biased signaling.

SUBMITTER: Sanchez-Soto M 

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

REPOSITORIES: biostudies-literature