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

Authors :
Sanchez-Soto M
Verma RK
Willette BKA
Gonye EC
Moore AM
Moritz AE
Boateng CA
Yano H
Free RB
Shi L
Sibley DR
Source :
Science signaling [Sci Signal] 2020 Feb 04; Vol. 13 (617). Date of Electronic Publication: 2020 Feb 04.
Publication Year :
2020

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 D <subscript>2</subscript> 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 other GPCRs similarly impaired β-arrestin recruitment while maintaining G protein signaling. To investigate the mechanism of this signaling bias, we used an active-state structure of the β <subscript>2</subscript> -adrenergic receptor (β2R) to build β2R-WT and β2R-Y199 <superscript>5.38</superscript> A models in complex with the full β2R agonist BI-167107 for molecular dynamics simulations. These analyses identified conformational rearrangements in β2R-Y199 <superscript>5.38</superscript> A that propagated from the extracellular ligand binding site to the intracellular surface, resulting in a modified orientation of the second intracellular loop in β2R-Y199 <superscript>5.38</superscript> A, which is predicted to affect its interactions with β-arrestin. Our findings provide a structural basis for how ligand binding site alterations can allosterically affect GPCR-transducer interactions and result in biased signaling.<br /> (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Details

Language :
English
ISSN :
1937-9145
Volume :
13
Issue :
617
Database :
MEDLINE
Journal :
Science signaling
Publication Type :
Academic Journal
Accession number :
32019899
Full Text :
https://doi.org/10.1126/scisignal.aaw5885