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TitleInactive structures of the vasopressin V2 receptor reveal distinct binding modes for Tolvaptan and Mambaquaretin toxin.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 3899, Year 2025
Publish dateApr 24, 2025
AuthorsAurélien Fouillen / Julien Bous / Pierre Couvineau / Hélène Orcel / Charline Mary / Lucie Lafleur / Timothé Pierre / Christiane Mendre / Nicolas Gilles / Gunnar Schulte / Sébastien Granier / Bernard Mouillac /
PubMed AbstractInhibitors 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 ...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.
External linksNat Commun / PubMed:40274867 / PubMed Central
MethodsEM (single particle)
Resolution2.5 - 3.8 Å
Structure data

EMDB-51985: Consensus refinement (Cryo-EM structure of inactive human arginine-vasopressin (AVP) V2 receptor (V2R) with tolvaptan)
Method: EM (single particle) / Resolution: 2.7 Å

EMDB-51986: Local refinement TVP-V2R (Cryo-EM structure of inactive human arginine-vasopressin (AVP) V2 receptor (V2R) with tolvaptan)
Method: EM (single particle) / Resolution: 2.5 Å

EMDB-51987: Local refinement Fab-Nb (Cryo-EM structure of inactive human arginine-vasopressin (AVP) V2 receptor (V2R) with tolvaptan)
Method: EM (single particle) / Resolution: 2.7 Å

51988

9hap

EMDB-51988, PDB-9hap:
Cryo-EM structure of inactive human arginine-vasopressin (AVP) V2 receptor (V2R) with tolvaptan
Method: EM (single particle) / Resolution: 2.5 Å

EMDB-52008: local refinment V2R-MQ39A (cryo-EM structure of inactive human arginine-vasopressin (AVP) V2 receptor (V2R) with Mambaquaretin1 K39A (MQK39A))
Method: EM (single particle) / Resolution: 2.5 Å

EMDB-52009: local refinement MQK39A (cryo-EM structure of inactive human arginine-vasopressin (AVP) V2 receptor (V2R) with Mambaquaretin1 K39A (MQK39A))
Method: EM (single particle) / Resolution: 3.8 Å

EMDB-52010: Focused refinement Fab-Nb (cryo-EM structure of inactive human arginine-vasopressin (AVP) V2 receptor (V2R) with Mambaquaretin1 K39A (MQK39A))
Method: EM (single particle) / Resolution: 2.5 Å

EMDB-52011: consensus refinement (cryo-EM structure of inactive human arginine-vasopressin (AVP) V2 receptor (V2R) with Mambaquaretin1 K39A (MQK39A))
Method: EM (single particle) / Resolution: 2.7 Å

52012

9hb3

EMDB-52012, PDB-9hb3:
cryo-EM structure of inactive human arginine-vasopressin (AVP) V2 receptor (V2R) with Mambaquaretin1 K39A (MQK39A)
Method: EM (single particle) / Resolution: 2.5 Å

Chemicals

PDB-1it8:
Crystal structure of archaeosine tRNA-guanine transglycosylase from Pyrococcus horikoshii complexed with archaeosine precursor, preQ0

Source
  • homo sapiens (human)
  • escherichia coli (E. coli)
  • dendroaspis angusticeps (eastern green mamba)
KeywordsMEMBRANE PROTEIN / GPCR / V2R / TVP / tolvaptan

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