Journal Article

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

Couvineau, Pierre, Lafleur, Lucie, Fouillen, Aurélien, Karolinska Institutet [Stockholm], Mendre, Christiane, Mary, Charline, Pierre, Timothé, Schulte, Gunnar, Fondation de la Recherche Médicale FRM (EQU202203014649)European Community Horizon-MSCA-2021-PF-01Swedish Research Council (2019-01190; 2024-02515)Swedish Cancer Society (20 1102 PjF; 23 2825 Pj)Novo Nordisk Foundation (NFF22OC0078104)Swedish Society for Medical Research (PG-23- 0321), ANR-22-CE44-0021,V2Cure,Vers des composés plus sélectifs ciblant un récepteur couplé aux protéine G prototypique, le récepteur V2 de la vasopressine, Granier, Sébastien, Gilles, Nicolas, ANR-19-CE11-0014,StrainV2,Détermination de la structure tridimensionnelle des conformations actives et inactives du récepteur V2 de la vasopressine, Bous, Julien, Centre de Biologie Structurale [Montpellier] (CBS) ; Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut de Génomique Fonctio

2025

Overview

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.

• Publisher: Nature Publishing Group,CCSD,Nature Publishing Group UK,Nature Portfolio
• Subject: 101/28 / 631/154/436/2387 / 631/45/612/194 / 631/535/1258/1259 / 96 / 96/33 / Animals / Antidiuretic Hormone Receptor Antagonists - chemistry / Antidiuretic Hormone Receptor Antagonists - metabolism / Antidiuretic Hormone Receptor Antagonists - pharmacology / Argipressin / Binding Sites / Biochemistry, Molecular Biology / Cryoelectron Microscopy / Drug development / Elapid Venoms - chemistry / Elapid Venoms - metabolism / Elapid Venoms - pharmacology / Electron microscopy / HEK293 Cells / Homeostasis / Human health and pathology / Humanities and Social Sciences / Humans / Hyponatremia / Inverse agonists / Kidney diseases / Kidneys / Life Sciences / Models, Molecular / Molecular modelling / multidisciplinary / Pharmaceutical sciences / Pharmacology / Polycystic kidney / Protein Binding / Protein structure / Proteins / Receptors / Receptors, Vasopressin - chemistry / Receptors, Vasopressin - genetics / Receptors, Vasopressin - metabolism / Receptors, Vasopressin - ultrastructure / Residues / Science / Science (multidisciplinary) / Snakes / Structural Biology / Tolvaptan - chemistry / Tolvaptan - metabolism / Tolvaptan - pharmacology / Toxins / Transmembrane domains / Urology and Nephrology / Vasopressin / Vasopressin V2 receptors / Venom