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-Structure paper
Title | Structural insights into angiotensin receptor signaling modulation by balanced and biased agonists. |
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Journal, issue, pages | EMBO J, Vol. 42, Issue 11, Page e112940, Year 2023 |
Publish date | Jun 1, 2023 |
Authors | Dongqi 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 Abstract | 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 ...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 links | EMBO J / PubMed:37038975 / PubMed Central |
Methods | EM (single particle) |
Resolution | 2.9 Å |
Structure data | EMDB-31479, PDB-7f6g: |
Chemicals | ChemComp-NAG: ChemComp-CLR: |
Source |
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Keywords | MEMBRANE PROTEIN / GPCR / angiotensin receptor |