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TitleStructural insights into angiotensin receptor signaling modulation by balanced and biased agonists.
Journal, issue, pagesEMBO J, Vol. 42, Issue 11, Page e112940, Year 2023
Publish dateJun 1, 2023
AuthorsDongqi Zhang / Yongfeng Liu / Saheem A Zaidi / Lingyi Xu / Yuting Zhan / Anqi Chen / Jiangtao Guo / Xi-Ping Huang / Bryan L Roth / Vsevolod Katritch / Vadim Cherezov / Haitao Zhang /
PubMed AbstractThe peptide hormone angiotensin II regulates blood pressure mainly through the type 1 angiotensin II receptor AT R and its downstream signaling proteins G and β-arrestin. AT R blockers, clinically ...The peptide hormone angiotensin II regulates blood pressure mainly through the type 1 angiotensin II receptor AT R and its downstream signaling proteins G and β-arrestin. AT R blockers, clinically used as antihypertensive drugs, inhibit both signaling pathways, whereas AT R β-arrestin-biased agonists have shown great potential for the treatment of acute heart failure. Here, we present a cryo-electron microscopy (cryo-EM) structure of the human AT R in complex with a balanced agonist, Sar -AngII, and G protein at 2.9 Å resolution. This structure, together with extensive functional assays and computational modeling, reveals the molecular mechanisms for AT R signaling modulation and suggests that a major hydrogen bond network (MHN) inside the receptor serves as a key regulator of AT R signal transduction from the ligand-binding pocket to both G and β-arrestin pathways. Specifically, we found that the MHN mutations N111 A and N294 A induce biased signaling to G and β-arrestin, respectively. These insights should facilitate AT R structure-based drug discovery for the treatment of cardiovascular diseases.
External linksEMBO J / PubMed:37038975 / PubMed Central
MethodsEM (single particle)
Resolution2.9 Å
Structure data

EMDB-31479, PDB-7f6g:
Cryo-EM structure of human angiotensin receptor AT1R in complex Gq proteins and Sar1-AngII
Method: EM (single particle) / Resolution: 2.9 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-CLR:
CHOLESTEROL

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / GPCR / angiotensin receptor

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