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TitleStructural mechanism of TRPV5 inhibition by econazole.
Journal, issue, pagesStructure, Vol. 32, Issue 2, Page 148-156.e5, Year 2024
Publish dateFeb 1, 2024
AuthorsJosé J De Jesús-Pérez / Matthew Gabrielle / Sumiyya Raheem / Edwin C Fluck / Tibor Rohacs / Vera Y Moiseenkova-Bell /
PubMed AbstractThe calcium-selective TRPV5 channel activated by phosphatidylinositol 4,5-bisphosphate [PI(4,5)P] is involved in calcium homeostasis. Recently, cryoelectron microscopy (cryo-EM) provided molecular ...The calcium-selective TRPV5 channel activated by phosphatidylinositol 4,5-bisphosphate [PI(4,5)P] is involved in calcium homeostasis. Recently, cryoelectron microscopy (cryo-EM) provided molecular details of TRPV5 modulation by exogenous and endogenous molecules. However, the details of TRPV5 inhibition by the antifungal agent econazole (ECN) remain elusive due to the low resolution of the currently available structure. In this study, we employ cryo-EM to comprehensively examine how the ECN inhibits TRPV5. By combining our structural findings with site-directed mutagenesis, calcium measurements, electrophysiology, and molecular dynamics simulations, we determined that residues F472 and L475 on the S4 helix, along with residue W495 on the S5 helix, collectively constitute the ECN-binding site. Additionally, the structure of TRPV5 in the presence of ECN and PI(4,5)P, which does not show the bound activator, reveals a potential inhibition mechanism in which ECN competes with PI(4,5)P, preventing the latter from binding, and ultimately pore closure.
External linksStructure / PubMed:38141613 / PubMed Central
MethodsEM (single particle)
Resolution2.57 - 2.94 Å
Structure data

41217

8tf2

EMDB-41217, PDB-8tf2:
Wildtype rabbit TRPV5 into nanodiscs in Apo state
Method: EM (single particle) / Resolution: 2.57 Å

41218

8tf3

EMDB-41218, PDB-8tf3:
Wildtype rabbit TRPV5 into nanodiscs in complex with econazole
Method: EM (single particle) / Resolution: 2.94 Å

41219

8tf4

EMDB-41219, PDB-8tf4:
Wildtype rabbit TRPV5 into nanodiscs in the presence of PI(4,5)P2 and econazole
Method: EM (single particle) / Resolution: 2.86 Å

Chemicals

ChemComp-ERG:
ERGOSTEROL

ChemComp-CPL:
1-PALMITOYL-2-LINOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / phospholipid*YM

ChemComp-ECN:
1-[(2S)-2-[(4-CHLOROBENZYL)OXY]-2-(2,4-DICHLOROPHENYL)ETHYL]-1H-IMIDAZOLE

Source
  • oryctolagus cuniculus (rabbit)
KeywordsMEMBRANE PROTEIN / TRPV5 / TRP channel / Apo / econazole / PI(4 / 5)P2

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