7xj2 | pdb_00007xj2

Structure of human TRPV3_G573S in complex with Trpvicin in C4 symmetry

spinqualitylabelsall models 7xj2, resolution 3.64Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7xj2 is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.64Å Ligands: EQK Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease TRPV3_HUMAN Mutilating palmoplantar keratoderma with periorificial keratotic plaques. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. Function TRPV3_HUMAN Putative receptor-activated non-selective calcium permeant cation channel. It is activated by innocuous (warm) temperatures and shows an increased response at noxious temperatures greater than 39 degrees Celsius. Activation exhibits an outward rectification. May associate with TRPV1 and may modulate its activity. Is a negative regulator of hair growth and cycling: TRPV3-coupled signaling suppresses keratinocyte proliferation in hair follicles and induces apoptosis and premature hair follicle regression (catagen). Publication Abstract from PubMed The TRPV3 channel plays vital roles in skin physiology. Dysfunction of TRPV3 causes skin diseases, including Olmsted syndrome. However, the lack of potent and selective inhibitors impedes the validation of TRPV3 as a therapeutic target. In this study, we identified Trpvicin as a potent and subtype-selective inhibitor of TRPV3. Trpvicin exhibits pharmacological potential in the inhibition of itch and hair loss in mouse models. Cryogenic electron microscopy structures of TRPV3 and the pathogenic G573S mutant complexed with Trpvicin reveal detailed ligand-binding sites, suggesting that Trpvicin inhibits the TRPV3 channel by stabilizing it in a closed state. Our G573S mutant structures demonstrate that the mutation causes a dilated pore, generating constitutive opening activity. Trpvicin accesses additional binding sites inside the central cavity of the G573S mutant to remodel the channel symmetry and block the channel. Together, our results provide mechanistic insights into the inhibition of TRPV3 by Trpvicin and support TRPV3-related drug development. Structural basis of TRPV3 inhibition by an antagonist.,Fan J, Hu L, Yue Z, Liao D, Guo F, Ke H, Jiang D, Yang Y, Lei X Nat Chem Biol. 2023 Jan;19(1):81-90. doi: 10.1038/s41589-022-01166-5. Epub 2022 , Oct 27. PMID:36302896 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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