Distinctive Activation Mechanism for Angiotensin Receptor Revealed by a Synthetic Nanobody.

Abstract:

:The angiotensin II (AngII) type 1 receptor (AT1R) is a critical regulator of cardiovascular and renal function and is an important model for studies of G-protein-coupled receptor (GPCR) signaling. By stabilizing the receptor with a single-domain antibody fragment ("nanobody") discovered using a synthetic yeast-displayed library, we determined the crystal structure of active-state human AT1R bound to an AngII analog with partial agonist activity. The nanobody binds to the receptor's intracellular transducer pocket, stabilizing the large conformational changes characteristic of activated GPCRs. The peptide engages the AT1R through an extensive interface spanning from the receptor core to its extracellular face and N terminus, remodeling the ligand-binding cavity. Remarkably, the mechanism used to propagate conformational changes through the receptor diverges from other GPCRs at several key sites, highlighting the diversity of allosteric mechanisms among GPCRs. Our structure provides insight into how AngII and its analogs stimulate full or biased signaling, respectively.

journal_name

Cell

journal_title

Cell

authors

Wingler LM,McMahon C,Staus DP,Lefkowitz RJ,Kruse AC

doi

10.1016/j.cell.2018.12.006

subject

Has Abstract

pub_date

2019-01-24 00:00:00

pages

479-490.e12

issue

3

eissn

0092-8674

issn

1097-4172

pii

S0092-8674(18)31589-7

journal_volume

176

pub_type

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