Structural insights into angiotensin receptor signaling modulation by balanced and biased agonists

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

doi:10.15252/embj.2022112940

Structural insights into angiotensin receptor signaling modulation by balanced and biased agonists

EMBO J. 2023 Jun 1;42(11):e112940. doi: 10.15252/embj.2022112940. Epub 2023 Apr 11.

Authors

Dongqi Zhang^#¹, Yongfeng Liu^#^{2

3}, Saheem A Zaidi⁴, Lingyi Xu^{5

6}, Yuting Zhan¹, Anqi Chen¹, Jiangtao Guo^{5

6}, Xi-Ping Huang^{2

3}, Bryan L Roth^{2

3

7}, Vsevolod Katritch^{4

8}, Vadim Cherezov⁸, Haitao Zhang^{1

9}

Affiliations

¹ Hangzhou Institute of Innovative Medicine, Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
² Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
³ National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP), University of North Carolina School of Medicine, Chapel Hill, NC, USA.
⁴ Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, USA.
⁵ Department of Biophysics, Zhejiang University School of Medicine, Hangzhou, China.
⁶ Department of Neurology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
⁷ Division of Chemical Biology and Medicinal Chemistry, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
⁸ Department of Chemistry, Bridge Institute, University of Southern California, Los Angeles, CA, USA.
⁹ The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

^# Contributed equally.

Abstract

The peptide hormone angiotensin II regulates blood pressure mainly through the type 1 angiotensin II receptor AT₁ R and its downstream signaling proteins G_q and β-arrestin. AT₁ R blockers, clinically used as antihypertensive drugs, inhibit both signaling pathways, whereas AT₁ 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 AT₁ R in complex with a balanced agonist, Sar¹ -AngII, and G_q protein at 2.9 Å resolution. This structure, together with extensive functional assays and computational modeling, reveals the molecular mechanisms for AT₁ R signaling modulation and suggests that a major hydrogen bond network (MHN) inside the receptor serves as a key regulator of AT₁ R signal transduction from the ligand-binding pocket to both G_q and β-arrestin pathways. Specifically, we found that the MHN mutations N111^3.35 A and N294^7.45 A induce biased signaling to G_q and β-arrestin, respectively. These insights should facilitate AT₁ R structure-based drug discovery for the treatment of cardiovascular diseases.

Keywords: AT1R; BRET; Cryo-EM; Gq protein; biased signaling.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Angiotensin II* / chemistry
Angiotensin II* / metabolism
Angiotensin II* / pharmacology
Cryoelectron Microscopy
Humans
Receptors, Angiotensin / metabolism
Signal Transduction* / physiology
beta-Arrestins / metabolism

Substances

beta-Arrestins
Angiotensin II
Receptors, Angiotensin