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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

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

Published Date

  • January 24, 2019

Published In

Volume / Issue

  • 176 / 3

Start / End Page

  • 479 - 490.e12

PubMed ID

  • 30639100

Pubmed Central ID

  • 30639100

Electronic International Standard Serial Number (EISSN)

  • 1097-4172

Digital Object Identifier (DOI)

  • 10.1016/j.cell.2018.12.006

Language

  • eng

Conference Location

  • United States