Distinctive Activation Mechanism for Angiotensin Receptor Revealed by a Synthetic Nanobody

Cell. 2019 Jan 24;176(3):479-490.e12. doi: 10.1016/j.cell.2018.12.006. Epub 2019 Jan 10.


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.

Keywords: G protein-coupled receptor; GPCR; angiotensin receptor; biased agonism; nanobody; single-domain antibody; yeast display.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II
  • Angiotensin II Type 1 Receptor Blockers / metabolism
  • Arrestins / metabolism
  • HEK293 Cells
  • Humans
  • Immunoglobulin Fragments / pharmacology
  • Protein Conformation
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins
  • Receptor, Angiotensin, Type 1 / metabolism*
  • Receptors, G-Protein-Coupled / metabolism
  • Signal Transduction / drug effects
  • Single-Domain Antibodies / metabolism
  • Single-Domain Antibodies / pharmacology*
  • beta-Arrestins / metabolism


  • Angiotensin II Type 1 Receptor Blockers
  • Arrestins
  • GPR114 protein, mouse
  • Immunoglobulin Fragments
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins
  • Receptor, Angiotensin, Type 1
  • Receptors, G-Protein-Coupled
  • Single-Domain Antibodies
  • beta-Arrestins
  • Angiotensin II