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

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.

SUBMITTER: Zhang D

PROVIDER: S-EPMC10233375 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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

Zhang Dongqi D Liu Yongfeng Y Zaidi Saheem A SA Xu Lingyi L Zhan Yuting Y Chen Anqi A Guo Jiangtao J Huang Xi-Ping XP Roth Bryan L BL Katritch Vsevolod V Cherezov Vadim V Zhang Haitao H

The EMBO journal 20230411 11

The peptide hormone angiotensin II regulates blood pressure mainly through the type 1 angiotensin II receptor AT1 R and its downstream signaling proteins Gq 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 AT<s ...[more]

PMID: 37038975

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Project description:BackgroundSeven transmembrane receptors (7TMRs) can adopt different active conformations facilitating a selective activation of either G protein or ?-arrestin-dependent signaling pathways. This represents an opportunity for development of novel therapeutics targeting selective biological effects of a given receptor. Several studies on pathway separation have been performed, many of these on the Angiotensin II type 1 receptor (AT1R). It has been shown that certain ligands or mutations facilitate internalization and/or recruitment of ?-arrestins without activation of G proteins. However, the underlying molecular mechanisms remain largely unresolved. For instance, it is unclear whether such selective G protein-uncoupling is caused by a lack of ability to interact with G proteins or rather by an increased ability of the receptor to recruit ?-arrestins. Since uncoupling of G proteins by increased ability to recruit ?-arrestins could lead to different cellular or in vivo outcomes than lack of ability to interact with G proteins, it is essential to distinguish between these two mechanisms.Methodology/principal findingsWe studied five AT1R mutants previously published to display pathway separation: D74N, DRY/AAY, Y292F, N298A, and Y302F (Ballesteros-Weinstein numbering: 2.50, 3.49-3.51, 7.43, 7.49, and 7.53). We find that D74N, DRY/AAY, and N298A mutants are more prone to ?-arrestin recruitment than WT. In contrast, receptor mutants Y292F and Y302F showed impaired ability to recruit ?-arrestin in response to Sar1-Ile4-Ile8 (SII) Ang II, a ligand solely activating the ?-arrestin pathway.Conclusions/significanceOur analysis reveals that the underlying conformations induced by these AT1R mutants most likely represent principally different mechanisms of uncoupling the G protein, which for some mutants may be due to their increased ability to recruit ?-arrestin2. Hereby, these findings have important implications for drug discovery and 7TMR biology and illustrate the necessity of uncovering the exact molecular determinants for G protein-coupling and ?-arrestin recruitment, respectively.

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

Publications

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

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