Inactive structures of the vasopressin V2 receptor reveal distinct binding modes for Tolvaptan and Mambaquaretin toxin

Aurélien Fouillen, Julien Bous, Pierre Couvineau, Hélène Orcel, Charline Mary, Lucie Lafleur, Timothé Pierre, Christiane Mendre, Nicolas Gilles, Gunnar Schulte (), Sébastien Granier () and Bernard Mouillac ()
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Aurélien Fouillen: Université de Montpellier, CNRS, INSERM
Julien Bous: Biomedicum
Pierre Couvineau: Université de Montpellier, CNRS, INSERM
Hélène Orcel: Université de Montpellier, CNRS, INSERM
Charline Mary: Université de Montpellier, CNRS, INSERM
Lucie Lafleur: Université de Montpellier, CNRS, INSERM
Timothé Pierre: Université de Montpellier, CNRS, INSERM
Christiane Mendre: Université de Montpellier, CNRS, INSERM
Nicolas Gilles: Université Paris Saclay, CEA, INRAE
Gunnar Schulte: Biomedicum
Sébastien Granier: Université de Montpellier, CNRS, INSERM
Bernard Mouillac: Université de Montpellier, CNRS, INSERM

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Inhibitors of the arginine-vasopressin (AVP) V2 receptor (V2R) are key therapeutic compounds for treating hyponatremia or polycystic kidney diseases. Rational drug design based on experimental G protein-coupled receptor structures is a powerful avenue to develop better drugs. So far, the lack of inhibitor-bound V2R structures has impaired this strategy. Here we describe the cryo-electron microscopy structures of the V2R in complex with two selective inverse agonists, the non-peptide Tolvaptan (TVP) and the green mamba snake Mambaquaretin toxin (MQ1). Both ligands bind into the orthosteric binding site but with substantial differences. TVP binds deeper than MQ1, and directly contacts the toggle switch residue W2846.48 in the transmembrane domain 6. The Kunitz-fold toxin displays extensive contacts with extracellular and transmembrane residues. As anticipated from TVP and MQ1 pharmacological properties, both structures represent inactive V2R conformations. Their comparison with those of the active AVP-bound V2R reveals the molecular mechanisms modulating receptor activity. The mini-protein MQ1-bound V2R structure suggests a new pharmacology approach for treating water homeostasis and renal diseases.

Date: 2025
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DOI: 10.1038/s41467-025-59114-5

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