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Structure paper

TitleStructural mechanisms of TRPV6 inhibition by ruthenium red and econazole.
Journal, issue, pagesNat Commun, Vol. 12, Issue 1, Page 6284, Year 2021
Publish dateNov 1, 2021
AuthorsArthur Neuberger / Kirill D Nadezhdin / Alexander I Sobolevsky /
PubMed AbstractTRPV6 is a calcium-selective ion channel implicated in epithelial Ca uptake. TRPV6 inhibitors are needed for the treatment of a broad range of diseases associated with disturbed calcium homeostasis, ...TRPV6 is a calcium-selective ion channel implicated in epithelial Ca uptake. TRPV6 inhibitors are needed for the treatment of a broad range of diseases associated with disturbed calcium homeostasis, including cancers. Here we combine cryo-EM, calcium imaging, and mutagenesis to explore molecular bases of human TRPV6 inhibition by the antifungal drug econazole and the universal ion channel blocker ruthenium red (RR). Econazole binds to an allosteric site at the channel's periphery, where it replaces a lipid. In contrast, RR inhibits TRPV6 by binding in the middle of the ion channel's selectivity filter and plugging its pore like a bottle cork. Despite different binding site locations, both inhibitors induce similar conformational changes in the channel resulting in closure of the gate formed by S6 helices bundle crossing. The uncovered molecular mechanisms of TRPV6 inhibition can guide the design of a new generation of clinically useful inhibitors.
External linksNat Commun / PubMed:34725357 / PubMed Central
MethodsEM (single particle)
Resolution2.43 - 2.85 Å
Structure data

24890

7s88

EMDB-24890, PDB-7s88:
Open apo-state cryo-EM structure of human TRPV6 in glyco-diosgenin detergent
Method: EM (single particle) / Resolution: 2.69 Å

24891

7s89

EMDB-24891, PDB-7s89:
Open apo-state cryo-EM structure of human TRPV6 in cNW11 nanodiscs
Method: EM (single particle) / Resolution: 2.54 Å

24892

7s8b

EMDB-24892, PDB-7s8b:
Cryo-EM structure of human TRPV6 in complex with channel blocker ruthenium red
Method: EM (single particle) / Resolution: 2.43 Å

24893

7s8c

EMDB-24893, PDB-7s8c:
Cryo-EM structure of human TRPV6 in complex with inhibitor econazole
Method: EM (single particle) / Resolution: 2.85 Å

Chemicals

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

ChemComp-PCW:
1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / DOPC, phospholipid*YM

ChemComp-POV:
(2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / phospholipid*YM

ChemComp-CA:
Unknown entry

ChemComp-HOH:
WATER

ChemComp-R2R:
ruthenium(6+) azanide pentaamino(oxido)ruthenium (1/4/2)

ChemComp-ECL:
1-[(2R)-2-[(4-chlorobenzyl)oxy]-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole

ChemComp-CL:
Unknown entry

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / Transient Receptor Potential V Family Member 6 / TRP / channel / apo / open / human / TRPV6 / cNW11 / nanodiscs / ruthenium red / channel blocker / antagonist / econazole / inhibitor

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