Journal
SCIENCE
Volume 367, Issue 6480, Pages 888-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aay9813
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Funding
- Sigrid Juselius Foundation
- International Human Frontier Science Program Organization [LT000916/2018-L]
- Mandel Center for Hypertension and Atherosclerosis at Duke
- Vallee Foundation
- Smith Family Foundation
- NIH [R01GM127359, R01HL16037, DP5OD021345]
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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 beta-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 beta-arrestin but not heterotrimeric G(q) protein signaling.
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