Inactive structures of the vasopressin V2 receptor reveal distinct binding modes for Tolvaptan and Mambaquaretin toxin
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 W284<sup>6.48</sup> 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.
Authors
- Pierre Thibault (ORCID: https://orcid.org/0000-0001-5993-0331)
- Christiane Mendre (ORCID: https://orcid.org/0000-0002-3111-2131)
- Bernard Mouillac (ORCID: https://orcid.org/0000-0002-3906-8673)
- Aurélien Fouillen (ORCID: https://orcid.org/0000-0002-0326-9932)
- Pierre Couvineau (ORCID: https://orcid.org/0000-0002-4905-7740)
- Charline Mary (ORCID: https://orcid.org/0000-0003-3056-8839)
- Sébastien Granier (ORCID: https://orcid.org/0000-0003-1550-3658)
- Julien Bous (ORCID: https://orcid.org/0000-0002-3459-7592)
- Nicolas Gilles (ORCID: https://orcid.org/0000-0001-6853-9764)
- Gunnar Schulte (ORCID: https://orcid.org/0000-0002-2700-7013)
- Hélène Orcel (ORCID: https://orcid.org/0000-0002-8699-088X)
- L Lafleur
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université de Montpellier (FR)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- Université Paris-Saclay (FR)
- Karolinska Institutet (SE)
- Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR)
- Centre de Biologie Structurale (FR)
- Maison de la Simulation (FR)
- CEA Paris-Saclay (FR)
- Institut de Génomique Fonctionnelle (FR)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-04-24
- DOI
- https://doi.org/10.1038/s41467-025-59114-5
- Citations
- 3
- Primary Topic
- Electrolyte and hormonal disorders
- Type
- article
- Field-Weighted Citation Impact
- 4.56
Funders
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Cancerfonden
- Svenska Sällskapet för Medicinsk Forskning
- Karolinska Institutet
- Novo Nordisk
- Vetenskapsrådet
- Centre National de la Recherche Scientifique
- Université de Montpellier