7F6G

Cryo-EM structure of human angiotensin receptor AT1R in complex Gq proteins and Sar1-AngII

Summary for 7F6G

• Entry DOI: 10.2210/pdb7f6g/pdb
• EMDB information: 31479
• Descriptor: Angiotensin receptor AT1R, SAR1-AngII, Guanine nucleotide-binding protein G(q) subunit alpha, ... (7 entities in total)
• Functional Keywords: gpcr, angiotensin receptor, membrane protein
• Biological source: Homo sapiens; More
• Total number of polymer chains: 5
• Total formula weight: 176983.43

Authors

Zhang, D.,Xu, L.,Zhan, Y.,Guo, J.,Zhang, H. (deposition date: 2021-06-25, release date: 2023-03-29, Last modification date: 2024-10-16)

Primary citation

Zhang, D.,Liu, Y.,Zaidi, S.A.,Xu, L.,Zhan, Y.,Chen, A.,Guo, J.,Huang, X.P.,Roth, B.L.,Katritch, V.,Cherezov, V.,Zhang, H.
Structural insights into angiotensin receptor signaling modulation by balanced and biased agonists.
Embo J., 42:e112940-e112940, 2023

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 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.

PubMed: 37038975
DOI: 10.15252/embj.2022112940

Experimental method

ELECTRON MICROSCOPY (2.9 Å)