2. Academic Validation
  3. Molecular basis of antagonism of the dimeric human arginine vasopressin receptor 1A

Molecular basis of antagonism of the dimeric human arginine vasopressin receptor 1A

  • Nat Commun. 2026 Jan 16;17(1):1622. doi: 10.1038/s41467-026-68331-5.
Peiyu Zhong # 1 2 3,  Bingxin Chu # 2 3,  Zijing Yu # 1 2 3,  Yu Qiao 2 3,  Yu Ding 4,  Yongdeng Zhang 5 6,  Xudong Wu 7 8
Affiliations

Affiliations

  • 1 Fudan University, Shanghai, China.
  • 2 State Key Laboratory of Gene Expression, Zhejiang Key Laboratory of Structural Biology, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China.
  • 3 Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China.
  • 4 School of Life Sciences, State Key Laboratory of Genetics and Development of Complex Phenotypes, Fudan University, Shanghai, China. [email protected].
  • 5 State Key Laboratory of Gene Expression, Zhejiang Key Laboratory of Structural Biology, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China. [email protected].
  • 6 Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China. [email protected].
  • 7 State Key Laboratory of Gene Expression, Zhejiang Key Laboratory of Structural Biology, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China. [email protected].
  • 8 Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China. [email protected].
  • # Contributed equally.
PMID: 41545407 DOI: 10.1038/s41467-026-68331-5
Abstract

Arginine vasopressin (AVP) and oxytocin (OT) are peptide Hormones critical for various physiological processes. Vasopressin Receptor 1 A (V1aR), a primary AVP target, is promising for central nervous system (CNS) disorders therapies, yet the mechanisms of antagonism and oligomerization remain poorly understood. Here, we present structures of human V1aR in its apo state and in complexes with antagonists: atosiban, balovaptan, and SRX246. Structural analyses reveal a dimeric V1aR assembly, validated by functional assays and imaging in cells. The apo structure shows a flat extracellular loop 2 (ECL2) with unpaired cysteines, undergoing significant conformational changes upon ligand binding. Antagonist-bound structures, combined with mutagenesis and radioligand binding assays, uncover distinct binding modes and key determinants for antagonism and selectivity. These findings provide a comprehensive understanding of V1aR assembly and dynamic regulation, offering valuable insights for structure-guided development of new antagonists targeting dimeric V1aR for CNS disorders.

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