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Structural basis of tolvaptan binding to the vasopressin V2 receptor

Abstract

The vasopressin V2 receptor (V2R) is a validated therapeutic target for autosomal dominant polycystic kidney disease (ADPKD), with tolvaptan being the first FDA-approved antagonist. Herein, we used Gaussian accelerated molecular dynamics simulations to investigate the spontaneous binding of tolvaptan to both active and inactive V2R conformations at the atomic-level. Overall, the binding process consists of two stages. Tolvaptan binds initially to extracellular loops 2 and 3 (ECL2/3) before overcoming an energy barrier to enter the pocket. Our simulations result highlighted key residues (e.g., R181, Y205, F287, F178) involved in this process, which were experimentally confirmed by site-directed mutagenesis. This work provides structural insights into tolvaptan-V2R interactions, potentially aiding the design of novel antagonists for V2R and other G protein-coupled receptors.

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Fig. 1: Tolvaptan first binds to the extracellular vestibule and finally stabilizes at a deeper binding pocket.
Fig. 2: The binding pathway of tolvaptan in active V2R in Run 1.
Fig. 3: The evolution of distance between the mass of the center of the benzene ring of W193ECL2 and the pyrrolidine ring of P301ECL3 over the simulation time in Run 1 and Run 5.
Fig. 4: Energy and the representative structures of tolvaptan in the binding pathway (Run 1).
Fig. 5: Energy contribution of the key residues for tolvaptan binding at the binding pocket.
Fig. 6: Sectional view of tolvaptan in the binding pocket.

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Acknowledgements

We thank Xiao-dan Zhu and Ying Ren for their excellent technical assistance. This work was supported by the National Natural Science Foundation of China (22377103, 22107090 and 22077110), the Natural Science Foundation of Jiangsu Province (BK20200106), the Major Basic Research Project of the Natural Science Research Foundation of the Jiangsu Higher Education Institutions (20KJA350001), the Natural Science Research Project of Jiangsu Universities (21KJB350009), and the Scientific Research Foundation for Talented Scholars in Xuzhou Medical University (D2020036, D2022002).

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DG and XCX initiated and supervised the research. HLL, HYZ and YXZ performed experiments and drafted the manuscript. HLL, DG and XCX participated in data analysis. HRX, ZSZ, KQF and XDC was involved in the discussion of the experiments. DG and XCX revised the manuscript. All authors have given approval to the final version of the manuscript.

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Correspondence to Xiao-chun Xiong or Dong Guo.

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Liu, Hl., Zhong, Hy., Zhang, Yx. et al. Structural basis of tolvaptan binding to the vasopressin V2 receptor. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01325-5

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