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
Celljournal_title
Cellauthors
Wingler LM,McMahon C,Staus DP,Lefkowitz RJ,Kruse ACdoi
10.1016/j.cell.2018.12.006subject
Has Abstractpub_date
2019-01-24 00:00:00pages
479-490.e12issue
3eissn
0092-8674issn
1097-4172pii
S0092-8674(18)31589-7journal_volume
176pub_type
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