7xj0

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Structure of human TRPV3 in complex with Trpvicin

Structural highlights

7xj0 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 2.53Å
Ligands:6OU, 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).[1] [2] [3]

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[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
4 reviews cite this structure
Transient Receptor Potential Channels and Itch.
Mahmoud et al. (2022)
3 more
4 other articles
No citations found

See Also

References

  1. ↑ Xu H, Ramsey IS, Kotecha SA, Moran MM, Chong JA, Lawson D, Ge P, Lilly J, Silos-Santiago I, Xie Y, DiStefano PS, Curtis R, Clapham DE. TRPV3 is a calcium-permeable temperature-sensitive cation channel. Nature. 2002 Jul 11;418(6894):181-6. Epub 2002 Jun 23. PMID:12077604 doi:http://dx.doi.org/10.1038/nature00882
  2. ↑ Smith GD, Gunthorpe MJ, Kelsell RE, Hayes PD, Reilly P, Facer P, Wright JE, Jerman JC, Walhin JP, Ooi L, Egerton J, Charles KJ, Smart D, Randall AD, Anand P, Davis JB. TRPV3 is a temperature-sensitive vanilloid receptor-like protein. Nature. 2002 Jul 11;418(6894):186-90. doi: 10.1038/nature00894. Epub 2002 Jun 23. PMID:12077606 doi:http://dx.doi.org/10.1038/nature00894
  3. ↑ Borbiro I, Lisztes E, Toth BI, Czifra G, Olah A, Szollosi AG, Szentandrassy N, Nanasi PP, Peter Z, Paus R, Kovacs L, Biro T. Activation of transient receptor potential vanilloid-3 inhibits human hair growth. J Invest Dermatol. 2011 Aug;131(8):1605-14. doi: 10.1038/jid.2011.122. Epub 2011 , May 19. PMID:21593771 doi:http://dx.doi.org/10.1038/jid.2011.122
  4. ↑ Fan J, Hu L, Yue Z, Liao D, Guo F, Ke H, Jiang D, Yang Y, Lei X. Structural basis of TRPV3 inhibition by an antagonist. Nat Chem Biol. 2023 Jan;19(1):81-90. PMID:36302896 doi:10.1038/s41589-022-01166-5

Contents


PDB ID 7xj0

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OCA

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