Angiotensin Analogs with Divergent Bias Stabilize Distinct Receptor Conformations. Cell 2019 Jan 24;176(3):468-478.e11
Date
01/15/2019Pubmed ID
30639099Pubmed Central ID
PMC6475118DOI
10.1016/j.cell.2018.12.005Scopus ID
2-s2.0-85060088316 (requires institutional sign-in at Scopus site) 171 CitationsAbstract
"Biased" G protein-coupled receptor (GPCR) agonists preferentially activate pathways mediated by G proteins or β-arrestins. Here, we use double electron-electron resonance spectroscopy to probe the changes that ligands induce in the conformational distribution of the angiotensin II type I receptor. Monitoring distances between 10 pairs of nitroxide labels distributed across the intracellular regions enabled mapping of four underlying sets of conformations. Ligands from different functional classes have distinct, characteristic effects on the conformational heterogeneity of the receptor. Compared to angiotensin II, the endogenous agonist, agonists with enhanced Gq coupling more strongly stabilize an "open" conformation with an accessible transducer-binding site. β-arrestin-biased agonists deficient in Gq coupling do not stabilize this open conformation but instead favor two more occluded conformations. These data suggest a structural mechanism for biased ligand action at the angiotensin receptor that can be exploited to rationally design GPCR-targeting drugs with greater specificity of action.
Author List
Wingler LM, Elgeti M, Hilger D, Latorraca NR, Lerch MT, Staus DP, Dror RO, Kobilka BK, Hubbell WL, Lefkowitz RJAuthor
Michael Lerch PhD Assistant Professor in the Biophysics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Angiotensin II Type 1 Receptor BlockersAngiotensin Receptor Antagonists
Angiotensins
Arrestins
Cell Line
Humans
Ligands
Protein Conformation
Receptor, Angiotensin, Type 1
Receptors, Angiotensin
Receptors, G-Protein-Coupled
Signal Transduction
Spectroscopy, Electron Energy-Loss
beta-Arrestins
