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Structure paper

TitleStructural basis for pharmacological modulation of the TRPC6 channel.
Journal, issue, pagesElife, Vol. 9, Year 2020
Publish dateMar 9, 2020
AuthorsYonghong Bai / Xinchao Yu / Hao Chen / Daniel Horne / Ryan White / Xiaosu Wu / Paul Lee / Yan Gu / Sudipa Ghimire-Rijal / Daniel C-H Lin / Xin Huang /
PubMed AbstractTransient receptor potential canonical (TRPC) proteins form nonselective cation channels that play physiological roles in a wide variety of cells. Despite growing evidence supporting the therapeutic ...Transient receptor potential canonical (TRPC) proteins form nonselective cation channels that play physiological roles in a wide variety of cells. Despite growing evidence supporting the therapeutic potential of TRPC6 inhibition in treating pathological cardiac and renal conditions, mechanistic understanding of TRPC6 function and modulation remains obscure. Here we report cryo-EM structures of TRPC6 in both antagonist-bound and agonist-bound states. The structures reveal two novel recognition sites for the small-molecule modulators corroborated by mutagenesis data. The antagonist binds to a cytoplasm-facing pocket formed by S1-S4 and the TRP helix, whereas the agonist wedges at the subunit interface between S6 and the pore helix. Conformational changes upon ligand binding illuminate a mechanistic rationale for understanding TRPC6 modulation. Furthermore, structural and mutagenesis analyses suggest several disease-related mutations enhance channel activity by disrupting interfacial interactions. Our results provide principles of drug action that may facilitate future design of small molecules to ameliorate TRPC6-mediated diseases.
External linksElife / PubMed:32149605 / PubMed Central
MethodsEM (single particle)
Resolution2.84 - 3.08 Å
Structure data

20953

6uz8

EMDB-20953, PDB-6uz8:
Cryo-EM structure of human TRPC6 in complex with agonist AM-0883
Method: EM (single particle) / Resolution: 2.84 Å

20954

6uza

EMDB-20954, PDB-6uza:
Cryo-EM structure of human TRPC6 in complex with antagonist AM-1473
Method: EM (single particle) / Resolution: 3.08 Å

Chemicals

ChemComp-SBM:
2-[[(2~{S})-2-decanoyloxy-3-dodecanoyloxy-propoxy]-oxidanyl-phosphoryl]oxyethyl-trimethyl-azanium

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

ChemComp-R0D:
(5-chloro-1'H-spiro[indole-3,4'-piperidin]-1'-yl)[(2R)-2,3-dihydro-1,4-benzodioxin-2-yl]methanone

ChemComp-R0G:
4-({(1R,2R)-2-[(3R)-3-aminopiperidin-1-yl]-2,3-dihydro-1H-inden-1-yl}oxy)benzonitrile

ChemComp-S9Y:
2-[[(2~{S})-2-decanoyloxypropoxy]-oxidanyl-phosphoryl]oxyethyl-trimethyl-azanium

ChemComp-SBJ:
[(2~{S})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-octanoyloxy-propan-2-yl] octadecanoate

Source
  • homo sapiens (human)
KeywordsTRANSPORT PROTEIN / TRP channel / Agonist / Antagonist

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