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- PDB-7xj2: Structure of human TRPV3_G573S in complex with Trpvicin in C4 symmetry -

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Basic information

Entry
Database: PDB / ID: 7xj2
TitleStructure of human TRPV3_G573S in complex with Trpvicin in C4 symmetry
ComponentsFusion protein of Transient receptor potential cation channel subfamily V member 3 and 3C-GFP
KeywordsMEMBRANE PROTEIN / channel
Function / homology
Function and homology information


calcium channel activity / plasma membrane
Similarity search - Function
Transient receptor potential cation channel subfamily V member 1-4 / Transient receptor potential cation channel subfamily V / Ankyrin repeat / Ankyrin repeats (3 copies) / Ankyrin repeat profile. / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing domain superfamily / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
Chem-EQK / Transient receptor potential cation channel subfamily V member 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.64 Å
AuthorsFan, J. / Yue, Z. / Jiang, D. / Lei, X.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)21625201 China
CitationJournal: Nat Chem Biol / Year: 2023
Title: Structural basis of TRPV3 inhibition by an antagonist.
Authors: Junping Fan / Linghan Hu / Zongwei Yue / Daohong Liao / Fusheng Guo / Han Ke / Daohua Jiang / Yong Yang / Xiaoguang Lei /
Abstract: 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 ...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.
History
DepositionApr 14, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 9, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 16, 2022Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Jan 11, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year
Revision 1.3Jul 3, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond / em_admin / Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
B: Fusion protein of Transient receptor potential cation channel subfamily V member 3 and 3C-GFP
C: Fusion protein of Transient receptor potential cation channel subfamily V member 3 and 3C-GFP
A: Fusion protein of Transient receptor potential cation channel subfamily V member 3 and 3C-GFP
D: Fusion protein of Transient receptor potential cation channel subfamily V member 3 and 3C-GFP
hetero molecules


Theoretical massNumber of molelcules
Total (without water)485,3758
Polymers483,4624
Non-polymers1,9144
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Fusion protein of Transient receptor potential cation channel subfamily V member 3 and 3C-GFP


Mass: 120865.406 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Details: The domain (792-799) is PreScission Site. The rest domain (800-1033) is corresponding to this sfGFP (2-235 amino acids).
Source: (gene. exp.) Homo sapiens (human) / Gene: TRPV3 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: B2KYM6
#2: Chemical
ChemComp-EQK / N-[5-[2-(2-cyanopropan-2-yl)pyridin-4-yl]-4-(trifluoromethyl)-1,3-thiazol-2-yl]-4,6-dimethoxy-pyrimidine-5-carboxamide


Mass: 478.448 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C20H17F3N6O3S / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: TRPV3 in complex with an antagonist / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.36 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK293
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.17.1_3660: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.64 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 48492 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00418848
ELECTRON MICROSCOPYf_angle_d0.58925679
ELECTRON MICROSCOPYf_dihedral_angle_d21.3522614
ELECTRON MICROSCOPYf_chiral_restr0.0383066
ELECTRON MICROSCOPYf_plane_restr0.0033149

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