Fouillen Aurélien, Bous Julien, Couvineau Pierre, Orcel Hélène, Mary Charline, Lafleur Lucie, Pierre Timothé, Mendre Christiane, Gilles Nicolas, Schulte Gunnar, Granier Sébastien, Mouillac Bernard
Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier cedex 5, France.
Karolinska Institutet, Department Physiology & Pharmacology, Sec Receptor Biology & Signaling, Biomedicum, Stockholm, Sweden.
Nat Commun. 2025 Apr 24;16(1):3899. doi: 10.1038/s41467-025-59114-5.
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 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.
精氨酸加压素（AVP）V2受体（V2R）抑制剂是治疗低钠血症或多囊肾病的关键治疗化合物。基于实验性G蛋白偶联受体结构的合理药物设计是开发更好药物的有力途径。到目前为止，缺乏与抑制剂结合的V2R结构阻碍了这一策略。在这里，我们描述了V2R与两种选择性反向激动剂——非肽托伐普坦（TVP）和绿曼巴蛇曼巴夸雷汀毒素（MQ1）复合物的冷冻电子显微镜结构。两种配体都结合到正构结合位点，但存在显著差异。TVP比MQ1结合得更深，并直接接触跨膜结构域6中的切换开关残基W284。库尼茨折叠毒素与细胞外和跨膜残基有广泛接触。正如从TVP和MQ1的药理特性所预期的那样，这两种结构都代表无活性的V2R构象。将它们与活性AVP结合的V2R结构进行比较，揭示了调节受体活性的分子机制。与微型蛋白MQ1结合的V2R结构为治疗水平衡和肾脏疾病提出了一种新的药理学方法。
