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TitleStructural basis for human TRPC5 channel inhibition by two distinct inhibitors.
Journal, issue, pagesElife, Vol. 10, Year 2021
Publish dateMar 8, 2021
AuthorsKangcheng Song / Miao Wei / Wenjun Guo / Li Quan / Yunlu Kang / Jing-Xiang Wu / Lei Chen /
PubMed AbstractTRPC5 channel is a nonselective cation channel that participates in diverse physiological processes. TRPC5 inhibitors show promise in the treatment of anxiety disorder, depression, and kidney disease. ...TRPC5 channel is a nonselective cation channel that participates in diverse physiological processes. TRPC5 inhibitors show promise in the treatment of anxiety disorder, depression, and kidney disease. However, the binding sites and inhibitory mechanism of TRPC5 inhibitors remain elusive. Here, we present the cryo-EM structures of human TRPC5 in complex with two distinct inhibitors, namely clemizole and HC-070, to the resolution of 2.7 Å. The structures reveal that clemizole binds inside the voltage sensor-like domain of each subunit. In contrast, HC-070 is wedged between adjacent subunits and replaces the glycerol group of a putative diacylglycerol molecule near the extracellular side. Moreover, we found mutations in the inhibitor binding pockets altered the potency of inhibitors. These structures suggest that both clemizole and HC-070 exert the inhibitory functions by stabilizing the ion channel in a nonconductive closed state. These results pave the way for further design and optimization of inhibitors targeting human TRPC5.
External linksElife / PubMed:33683200 / PubMed Central
MethodsEM (single particle)
Resolution2.7 - 3.0 Å
Structure data

30575

7d4p

EMDB-30575, PDB-7d4p:
Structure of human TRPC5 in complex with clemizole
Method: EM (single particle) / Resolution: 2.7 Å

30576

7d4q

EMDB-30576, PDB-7d4q:
Structure of human TRPC5 in complex with HC-070
Method: EM (single particle) / Resolution: 2.74 Å

30987

7e4t

EMDB-30987, PDB-7e4t:
Human TRPC5 apo state structure at 3 angstrom
Method: EM (single particle) / Resolution: 3.0 Å

Chemicals

ChemComp-GX0:
1-[(4-chlorophenyl)methyl]-2-(pyrrolidin-1-ylmethyl)benzimidazole / antagonist*YM / Clemizole

ChemComp-PTY:
PHOSPHATIDYLETHANOLAMINE / phospholipid*YM / Phosphatidylethanolamine

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

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

ChemComp-ZN:
Unknown entry

ChemComp-CA:
Unknown entry

ChemComp-YZY:
(2S)-2-(hexadecanoyloxy)-3-hydroxypropyl (9Z)-octadec-9-enoate

ChemComp-GWR:
8-(3-chloranylphenoxy)-7-[(4-chlorophenyl)methyl]-3-methyl-1-(3-oxidanylpropyl)purine-2,6-dione

Source
  • homo sapiens (human)
KeywordsMETAL TRANSPORT / clemizole / TRPC5 / trpc / HC-070

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