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TitleHuman TRPC5 structures reveal interaction of a xanthine-based TRPC1/4/5 inhibitor with a conserved lipid binding site.
Journal, issue, pagesCommun Biol, Vol. 3, Issue 1, Page 704, Year 2020
Publish dateNov 23, 2020
AuthorsDavid J Wright / Katie J Simmons / Rachel M Johnson / David J Beech / Stephen P Muench / Robin S Bon /
PubMed AbstractTRPC1/4/5 channels are non-specific cation channels implicated in a wide variety of diseases, and TRPC1/4/5 inhibitors have recently entered clinical trials. However, fundamental and translational ...TRPC1/4/5 channels are non-specific cation channels implicated in a wide variety of diseases, and TRPC1/4/5 inhibitors have recently entered clinical trials. However, fundamental and translational studies require a better understanding of TRPC1/4/5 channel regulation by endogenous and exogenous factors. Although several potent and selective TRPC1/4/5 modulators have been reported, the paucity of mechanistic insights into their modes-of-action remains a barrier to the development of new chemical probes and drug candidates. Xanthine-based modulators include the most potent and selective TRPC1/4/5 inhibitors described to date, as well as TRPC5 activators. Our previous studies suggest that xanthines interact with a, so far, elusive pocket of TRPC1/4/5 channels that is essential to channel gating. Here we report the structure of a small-molecule-bound TRPC1/4/5 channel-human TRPC5 in complex with the xanthine Pico145-to 3.0 Å. We found that Pico145 binds to a conserved lipid binding site of TRPC5, where it displaces a bound phospholipid. Our findings explain the mode-of-action of xanthine-based TRPC1/4/5 modulators, and suggest a structural basis for TRPC1/4/5 modulation by endogenous factors such as (phospho)lipids and Zn ions. These studies lay the foundations for the structure-based design of new generations of TRPC1/4/5 modulators.
External linksCommun Biol / PubMed:33230284 / PubMed Central
MethodsEM (single particle)
Resolution2.8 - 3.0 Å
Structure data

10903

6ysn

EMDB-10903, PDB-6ysn:
Human TRPC5 in complex with Pico145 (HC-608)
Method: EM (single particle) / Resolution: 3.0 Å

EMDB-10909:
Human TRPC5 in the presence of 50 uM Pico145 (HC-608)
Method: EM (single particle) / Resolution: 2.9 Å

EMDB-10910:
Human TRPC5 in the presence of 20 uM ZnCl2
Method: EM (single particle) / Resolution: 2.8 Å

Chemicals

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

Source
  • escherichia coli (strain k12) (bacteria)
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / Ion channel / small molecule / inhibitor / tetramer

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