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TitleStructural Pharmacology of TRPV4 Antagonists.
Journal, issue, pagesAdv Sci (Weinh), Page e2401583, Year 2024
Publish dateApr 24, 2024
AuthorsJunping Fan / Chang Guo / Daohong Liao / Han Ke / Jing Lei / Wenjun Xie / Yuliang Tang / Makoto Tominaga / Zhuo Huang / Xiaoguang Lei /
PubMed AbstractThe nonselective calcium-permeable Transient Receptor Potential Cation Channel Subfamily V Member4 (TRPV4) channel regulates various physiological activities. Dysfunction of TRPV4 is linked to many ...The nonselective calcium-permeable Transient Receptor Potential Cation Channel Subfamily V Member4 (TRPV4) channel regulates various physiological activities. Dysfunction of TRPV4 is linked to many severe diseases, including edema, pain, gastrointestinal disorders, lung diseases, and inherited neurodegeneration. Emerging TRPV4 antagonists show potential clinical benefits. However, the molecular mechanisms of TRPV4 antagonism remain poorly understood. Here, cryo-electron microscopy (cryo-EM) structures of human TRPV4 are presented in-complex with two potent antagonists, revealing the detailed binding pockets and regulatory mechanisms of TRPV4 gating. Both antagonists bind to the voltage-sensing-like domain (VSLD) and stabilize the channel in closed states. These two antagonists induce TRPV4 to undergo an apparent fourfold to twofold symmetry transition. Moreover, it is demonstrated that one of the antagonists binds to the VSLD extended pocket, which differs from the canonical VSLD pocket. Complemented with functional and molecular dynamics simulation results, this study provides crucial mechanistic insights into TRPV4 regulation by small-molecule antagonists, which may facilitate future drug discovery targeting TRPV4.
External linksAdv Sci (Weinh) / PubMed:38659239
MethodsEM (single particle)
Resolution3.21 - 3.74 Å
Structure data

36659

8ju5

EMDB-36659, PDB-8ju5:
Structure of human TRPV4 with antagonist A1
Method: EM (single particle) / Resolution: 3.74 Å

36660

8ju6

EMDB-36660, PDB-8ju6:
Structure of human TRPV4 with antagonist GSK279
Method: EM (single particle) / Resolution: 3.45 Å

36675

8jvi

EMDB-36675, PDB-8jvi:
Structure of human TRPV4 with antagonist A2
Method: EM (single particle) / Resolution: 3.21 Å

36676

8jvj

EMDB-36676, PDB-8jvj:
Structure of human TRPV4 with antagonist A2 and RhoA
Method: EM (single particle) / Resolution: 3.44 Å

Chemicals


ChemComp, No image

ChemComp-F3L:
Unknown entry

ChemComp-XPW:
1-({(5S,7S)-3-[5-(2-hydroxypropan-2-yl)pyrazin-2-yl]-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl}methyl)-1H-benzimidazole-6-carbonitrile


ChemComp, No image

ChemComp-F9M:
Unknown entry

Source
  • homo sapiens (human)
  • synthetic construct (others)
KeywordsMEMBRANE PROTEIN / Channel

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