6UZA

Cryo-EM structure of human TRPC6 in complex with antagonist AM-1473

Summary for 6UZA

• Entry DOI: 10.2210/pdb6uza/pdb
• Related: 6UZ8
• EMDB information: 20953 20954
• Descriptor: Short transient receptor potential channel 6, 4-({(1R,2R)-2-[(3R)-3-aminopiperidin-1-yl]-2,3-dihydro-1H-inden-1-yl}oxy)benzonitrile, 2-[[(2~{S})-2-decanoyloxypropoxy]-oxidanyl-phosphoryl]oxyethyl-trimethyl-azanium, ... (5 entities in total)
• Functional Keywords: trp channel, antagonist, transport protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 398056.10

Authors

Bai, Y.,Yu, X.,Huang, X.,Chen, H. (deposition date: 2019-11-14, release date: 2020-03-18, Last modification date: 2024-10-16)

Primary citation

Bai, Y.,Yu, X.,Chen, H.,Horne, D.,White, R.,Wu, X.,Lee, P.,Gu, Y.,Ghimire-Rijal, S.,Lin, D.C.,Huang, X.
Structural basis for pharmacological modulation of the TRPC6 channel.
Elife, 9:-, 2020

PubMed Abstract: 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.

PubMed: 32149605
DOI: 10.7554/eLife.53311

Experimental method

ELECTRON MICROSCOPY (3.08 Å)