6OS1

Structure of synthetic nanobody-stabilized angiotensin II type 1 receptor bound to TRV023

Summary for 6OS1

• Entry DOI: 10.2210/pdb6os1/pdb
• Descriptor: Type-1 angiotensin II receptor,Soluble cytochrome b562 BRIL fusion protein, Nanobody Nb.AT110i1_le, TRV023 peptide, ... (6 entities in total)
• Functional Keywords: gpcr, membrane protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 65781.06

Authors

Wingler, L.M.,Staus, D.P.,Skiba, M.A.,McMahon, C.,Kleinhenz, A.L.W.,Lefkowitz, R.J.,Kruse, A.C. (deposition date: 2019-05-01, release date: 2020-02-19, Last modification date: 2023-10-11)

Primary citation

Wingler, L.M.,Skiba, M.A.,McMahon, C.,Staus, D.P.,Kleinhenz, A.L.W.,Suomivuori, C.M.,Latorraca, N.R.,Dror, R.O.,Lefkowitz, R.J.,Kruse, A.C.
Angiotensin and biased analogs induce structurally distinct active conformations within a GPCR.
Science, 367:888-892, 2020

PubMed Abstract: Biased agonists of G protein-coupled receptors (GPCRs) preferentially activate a subset of downstream signaling pathways. In this work, we present crystal structures of angiotensin II type 1 receptor (AT1R) (2.7 to 2.9 angstroms) bound to three ligands with divergent bias profiles: the balanced endogenous agonist angiotensin II (AngII) and two strongly β-arrestin-biased analogs. Compared with other ligands, AngII promotes more-substantial rearrangements not only at the bottom of the ligand-binding pocket but also in a key polar network in the receptor core, which forms a sodium-binding site in most GPCRs. Divergences from the family consensus in this region, which appears to act as a biased signaling switch, may predispose the AT1R and certain other GPCRs (such as chemokine receptors) to adopt conformations that are capable of activating β-arrestin but not heterotrimeric G protein signaling.

PubMed: 32079768
DOI: 10.1126/science.aay9813

Experimental method

X-RAY DIFFRACTION (2.794 Å)