6uz8 | pdb_00006uz8

Cryo-EM structure of human TRPC6 in complex with agonist AM-0883

spinqualitylabelsall models 6uz8, resolution 2.84Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6uz8 is a 4 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: R0D, SBM, Y01 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [TRPC6_HUMAN] Familial idiopathic steroid-resistant nephrotic syndrome with focal segmental hyalinosis. The disease is caused by mutations affecting the gene represented in this entry. Function [TRPC6_HUMAN] Thought to form a receptor-activated non-selective calcium permeant cation channel (PubMed:19936226, PubMed:23291369). Probably is operated by a phosphatidylinositol second messenger system activated by receptor tyrosine kinases or G-protein coupled receptors. Activated by diacylglycerol (DAG) in a membrane-delimited fashion, independently of protein kinase C (PubMed:26892346). Seems not to be activated by intracellular calcium store depletion. Publication Abstract from PubMed 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. Structural basis for pharmacological modulation of the TRPC6 channel.,Bai Y, Yu X, Chen H, Horne D, White R, Wu X, Lee P, Gu Y, Ghimire-Rijal S, Lin DC, Huang X Elife. 2020 Mar 9;9. pii: 53311. doi: 10.7554/eLife.53311. PMID:32149605 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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