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- EMDB-33216: Structure of human TRPV3_G573S in complex with Trpvicin in C2 symmetry -

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Basic information

Entry
Database: EMDB / ID: EMD-33216
TitleStructure of human TRPV3_G573S in complex with Trpvicin in C2 symmetry
Map data
Sample
  • Complex: TRPV3 in complex with an antagonist
    • Protein or peptide: Fusion protein of Transient receptor potential cation channel subfamily V member 3 and 3C-GFP
  • Ligand: [(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl] (~{Z})-octadec-9-enoate
  • Ligand: N-[5-[2-(2-cyanopropan-2-yl)pyridin-4-yl]-4-(trifluoromethyl)-1,3-thiazol-2-yl]-4,6-dimethoxy-pyrimidine-5-carboxamide
Keywordschannel / MEMBRANE PROTEIN
Function / homology
Function and homology information


calcium channel activity / 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
Transient receptor potential cation channel subfamily V member 3
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.93 Å
AuthorsFan J / Yue Z / Jiang D / Lei X
Funding support China, 1 items
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, 2022-
Header (metadata) releaseNov 9, 2022-
Map releaseNov 9, 2022-
UpdateJul 3, 2024-
Current statusJul 3, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_33216.png

Downloads & links

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Map

FileDownload / File: emd_33216.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.04 Å/pix.
x 320 pix.
= 332.8 Å		1.04 Å/pix.
x 320 pix.
= 332.8 Å		1.04 Å/pix.
x 320 pix.
= 332.8 Å

Surface

Projections

Slices (1/3)

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.04 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.43
Minimum - Maximum-2.9306943 - 5.41496
Average (Standard dev.)0.001217867 (±0.10300464)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 332.8 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_33216_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_33216_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : TRPV3 in complex with an antagonist

EntireName: TRPV3 in complex with an antagonist
Components
  • Complex: TRPV3 in complex with an antagonist
    • Protein or peptide: Fusion protein of Transient receptor potential cation channel subfamily V member 3 and 3C-GFP
  • Ligand: [(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl] (~{Z})-octadec-9-enoate
  • Ligand: N-[5-[2-(2-cyanopropan-2-yl)pyridin-4-yl]-4-(trifluoromethyl)-1,3-thiazol-2-yl]-4,6-dimethoxy-pyrimidine-5-carboxamide

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Supramolecule #1: TRPV3 in complex with an antagonist

SupramoleculeName: TRPV3 in complex with an antagonist / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 360 KDa

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Macromolecule #1: Fusion protein of Transient receptor potential cation channel sub...

MacromoleculeName: Fusion protein of Transient receptor potential cation channel subfamily V member 3 and 3C-GFP
type: protein_or_peptide / ID: 1
Details: The domain (792-799) is PreScission Site. The rest domain (800-1033) is corresponding to this sfGFP (2-235 amino acids).,The domain (792-799) is PreScission Site. The rest domain (800-1033) ...Details: The domain (792-799) is PreScission Site. The rest domain (800-1033) is corresponding to this sfGFP (2-235 amino acids).,The domain (792-799) is PreScission Site. The rest domain (800-1033) is corresponding to this sfGFP (2-235 amino acids).
Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 120.865406 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MKAHPKEMVP LMGKRVAAPS GNPAILPEKR PAEITPTKKS AHFFLEIEGF EPNPTVAKTS PPVFSKPMDS NIRQCISGNC DDMDSPQSP QDDVTETPSN PNSPSAQLAK EEQRRKKRRL KKRIFAAVSE GCVEELVELL VELQELCRRR HDEDVPDFLM H KLTASDTG ...String:
MKAHPKEMVP LMGKRVAAPS GNPAILPEKR PAEITPTKKS AHFFLEIEGF EPNPTVAKTS PPVFSKPMDS NIRQCISGNC DDMDSPQSP QDDVTETPSN PNSPSAQLAK EEQRRKKRRL KKRIFAAVSE GCVEELVELL VELQELCRRR HDEDVPDFLM H KLTASDTG KTCLMKALLN INPNTKEIVR ILLAFAEEND ILGRFINAEY TEEAYEGQTA LNIAIERRQG DIAALLIAAG AD VNAHAKG AFFNPKYQHE GFYFGETPLA LAACTNQPEI VQLLMEHEQT DITSRDSRGN NILHALVTVA EDFKTQNDFV KRM YDMILL RSGNWELETT RNNDGLTPLQ LAAKMGKAEI LKYILSREIK EKRLRSLSRK FTDWAYGPVS SSLYDLTNVD TTTD NSVLE ITVYNTNIDN RHEMLTLEPL HTLLHMKWKK FAKHMFFLSF CFYFFYNITL TLVSYYRPRE EEAIPHPLAL THKMG WLQL LGRMFVLIWA MCISVKEGIA IFLLRPSDLQ SILSDAWFHF VFFIQAVLVI LSVFLYLFAY KEYLACLVLA MALGWA NML YYTRGFQSMS MYSVMIQKVI LHDVLKFLFV YIVFLLGFGV ALASLIEKCP KDNKDCSSYG SFSDAVLELF KLTIGLG DL NIQQNSKYPI LFLFLLITYV ILTFVLLLNM LIALMGETVE NVSKESERIW RLQRARTILE FEKMLPEWLR SRFRMGEL C KVAEDDFRLC LRINEVKWTE WKTHVSFLNE DPGPVRRTAD FNKIQDSSRN NSKTTLNAFE EVEEFPETSV LEVLFQGPS KGEELFTGVV PILVELDGDV NGHKFSVRGE GEGDATNGKL TLKFICTTGK LPVPWPTLVT TLTYGVQCFS RYPDHMKRHD FFKSAMPEG YVQERTISFK DDGTYKTRAE VKFEGDTLVN RIELKGIDFK EDGNILGHKL EYNFNSHNVY ITADKQKNGI K ANFKIRHN VEDGSVQLAD HYQQNTPIGD GPVLLPDNHY LSTQSVLSKD PNEKRDHMVL LEFVTAAGIT HGMDEWSHPQ FE KGGGSGG GSGGSAWSHP QFEK

UniProtKB: Transient receptor potential cation channel subfamily V member 3

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Macromolecule #2: [(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyl...

MacromoleculeName: [(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl] (~{Z})-octadec-9-enoate
type: ligand / ID: 2 / Number of copies: 10 / Formula: 6OU
Molecular weightTheoretical: 717.996 Da
Chemical component information

ChemComp-6OU:
[(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl] (~{Z})-octadec-9-enoate / phospholipid*YM

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Macromolecule #3: N-[5-[2-(2-cyanopropan-2-yl)pyridin-4-yl]-4-(trifluoromethyl)-1,3...

MacromoleculeName: N-[5-[2-(2-cyanopropan-2-yl)pyridin-4-yl]-4-(trifluoromethyl)-1,3-thiazol-2-yl]-4,6-dimethoxy-pyrimidine-5-carboxamide
type: ligand / ID: 3 / Number of copies: 10 / Formula: EQK
Molecular weightTheoretical: 478.448 Da
Chemical component information

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

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.93 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 152978
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD

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