[English] 日本語
Yorodumi
- EMDB-70601: Structure of a constitutively open human TRPC3 mutant in the inhi... -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: EMDB / ID: EMD-70601
TitleStructure of a constitutively open human TRPC3 mutant in the inhibited state
Map data
Sample
  • Complex: human TRPC3 T573A/Delta 28 mutant/GSK417651A tetrameric complex
    • Protein or peptide: Short transient receptor potential channel 3
  • Ligand: UNKNOWN LIGAND
  • Ligand: (3,4-dihydroisoquinolin-2(1H)-yl)[2-(4-methoxyanilino)-1,3-thiazol-4-yl]methanone
KeywordsTRPC3 / cerebellar ataxia / moonwalker / MEMBRANE PROTEIN
Function / homology
Function and homology information


positive regulation of cardiac muscle hypertrophy in response to stress / Role of second messengers in netrin-1 signaling / store-operated calcium channel activity / Effects of PIP2 hydrolysis / Elevation of cytosolic Ca2+ levels / inositol 1,4,5 trisphosphate binding / cation channel complex / calcium-activated cation channel activity / TRP channels / response to ATP ...positive regulation of cardiac muscle hypertrophy in response to stress / Role of second messengers in netrin-1 signaling / store-operated calcium channel activity / Effects of PIP2 hydrolysis / Elevation of cytosolic Ca2+ levels / inositol 1,4,5 trisphosphate binding / cation channel complex / calcium-activated cation channel activity / TRP channels / response to ATP / phototransduction / positive regulation of calcium ion transport into cytosol / single fertilization / regulation of cytosolic calcium ion concentration / MECP2 regulates neuronal receptors and channels / response to calcium ion / calcium ion transmembrane transport / calcium channel activity / calcium ion transport / metal ion binding / plasma membrane
Similarity search - Function
Transient receptor potential channel, canonical 3 / Transient receptor ion channel domain / Transient receptor ion channel II / Transient receptor ion channel II / Transient receptor potential channel, canonical / Ankyrin repeats (3 copies) / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing domain superfamily ...Transient receptor potential channel, canonical 3 / Transient receptor ion channel domain / Transient receptor ion channel II / Transient receptor ion channel II / Transient receptor potential channel, canonical / Ankyrin repeats (3 copies) / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing domain superfamily / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
Short transient receptor potential channel 3
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsBell B / Baker ML / Cordero-Morales JF
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM149218 United States
CitationJournal: Sci Adv / Year: 2026
Title: Functional and structural basis of a hypermorphic TRPC3 variant.
Authors: Briar Bell / Angela M Jaramillo-Granada / Luis O Romero / Irene A Gutierrez / Venkata K P S Mallampalli / Guizhen Fan / Sameer Varma / Matthew L Baker / Irina I Serysheva / Valeria Vásquez ...Authors: Briar Bell / Angela M Jaramillo-Granada / Luis O Romero / Irene A Gutierrez / Venkata K P S Mallampalli / Guizhen Fan / Sameer Varma / Matthew L Baker / Irina I Serysheva / Valeria Vásquez / Julio F Cordero-Morales /
Abstract: Cerebellar ataxias are characterized by impaired motor coordination resulting from neuronal dysfunction within the cerebellum. The mechanisms underlying this pathology and its cerebellar-specific ...Cerebellar ataxias are characterized by impaired motor coordination resulting from neuronal dysfunction within the cerebellum. The mechanisms underlying this pathology and its cerebellar-specific neurodegeneration remain unknown. We uncover how a gain-of-function canonical transient receptor potential member 3 (TRPC3) mutation, coupled with a cerebellum-specific isoform, stabilizes the channel's open state, resists the leading inhibitor Pyr3, and drives calcium-dependent cell death. Restoring calcium homeostasis by expressing a Purkinje cell calcium pump improves cell viability. Transgenic expression of the TRPC3 hypermorphic variant in induces neurodegeneration, confirming its pathogenicity across species. Cryo-electron microscopy and molecular simulations reveal the structural basis for the stabilization of the cerebellar-specific TRPC3 variant in its open state and uncover a druggable allosteric inhibitory binding site. These findings provide an explanation for the vulnerability of cerebellar neurons in TRPC3-associated ataxias and highlight a site for therapeutic intervention.
History
DepositionMay 13, 2025-
Header (metadata) releaseMar 25, 2026-
Map releaseMar 25, 2026-
UpdateApr 8, 2026-
Current statusApr 8, 2026Processing site: RCSB / Status: Released

-
Structure visualization

Supplemental images

emd_70601.png

Downloads & links

-
Map

FileDownload / File: emd_70601.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.08 Å/pix.
x 300 pix.
= 324. Å		1.08 Å/pix.
x 300 pix.
= 324. Å		1.08 Å/pix.
x 300 pix.
= 324. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.08 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.051
Minimum - Maximum-0.27824366 - 0.4676135
Average (Standard dev.)0.0001795339 (±0.012099681)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 324.0 Å
α=β=γ: 90.0 °

-
Supplemental data

-
Half map: #2

Fileemd_70601_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Half map: #1

Fileemd_70601_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Sample components

-
Entire : human TRPC3 T573A/Delta 28 mutant/GSK417651A tetrameric complex

EntireName: human TRPC3 T573A/Delta 28 mutant/GSK417651A tetrameric complex
Components
  • Complex: human TRPC3 T573A/Delta 28 mutant/GSK417651A tetrameric complex
    • Protein or peptide: Short transient receptor potential channel 3
  • Ligand: UNKNOWN LIGAND
  • Ligand: (3,4-dihydroisoquinolin-2(1H)-yl)[2-(4-methoxyanilino)-1,3-thiazol-4-yl]methanone

-
Supramolecule #1: human TRPC3 T573A/Delta 28 mutant/GSK417651A tetrameric complex

SupramoleculeName: human TRPC3 T573A/Delta 28 mutant/GSK417651A tetrameric complex
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

-
Macromolecule #1: Short transient receptor potential channel 3

MacromoleculeName: Short transient receptor potential channel 3 / type: protein_or_peptide / ID: 1
Details: Transient Receptor Potential Canonical Channel 3 T573A/Delta 28 mutant/GSK417 tetrameric protein complex
Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 94.153156 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MEGSPSLRRM TVMREKGRRQ AVRGPAFMFN DRGTSLTAEE ERFLDAAEYG NIPVVRKMLE ESKTLNVNCV DYMGQNALQL AVGNEHLEV TELLLKKENL ARIGDALLLA ISKGYVRIVE AILNHPGFAA SKRLTLSPCE QELQDDDFYA YDEDGTRFSP D ITPIILAA ...String:
MEGSPSLRRM TVMREKGRRQ AVRGPAFMFN DRGTSLTAEE ERFLDAAEYG NIPVVRKMLE ESKTLNVNCV DYMGQNALQL AVGNEHLEV TELLLKKENL ARIGDALLLA ISKGYVRIVE AILNHPGFAA SKRLTLSPCE QELQDDDFYA YDEDGTRFSP D ITPIILAA HCQKYEVVHM LLMKGARIER PHDYFCKCGD CMEKQRHDSF SHSRSRINAY KGLASPAYLS LSSEDPVLTA LE LSNELAK LANIEKEFKN DYRKLSMQCK DFVVGVLDLC RDSEEVEAIL NGDLESAEPL EVHRHKASLS RVKLAIKYEV KKF VAHPNC QQQLLTIWYE NLSGLREQTI AIKCLVVLVV ALGLPFLAIG YWIAPCSRLG KILRSPFMKF VAHAASFIIF LGLL VFNAS DRFEGITTLP NITVTDYPKQ IFRVKTTQFT WTEMLIMVWV LGMMWSECKE LWLEGPREYI LQLWNVLDFG MLSIF IAAF TARFLAFLQA TKAQQYVDSY VQESDLSEVT LPPEIQYFTY ARDKWLPSDP QIISEGLYAI AVVLSFSRIA YILPAN ESF GPLQISLGRA VKDIFKFMVL FIMVFFAFMI GMFILYSYYL GAKVNAAFTT VEESFKTLFW SIFGLSEVTS VVLKYDH KF IENIGYVLYG IYNVTMVVVL LNMLIAMINS SYQEIEDDSD VEWKFARSKL WLSYFDDGKT LPPPFSLVPS PKSFVYFI M RIVNFPKCRR RRLQKDIEMG MGNSKSRQIM KRLIKRYVLK AQVDKENDEV NEGELKEIKQ DISSLRYELL EDKSQATEE LAILIHKLSE ISSLRYELLE

UniProtKB: Short transient receptor potential channel 3

-
Macromolecule #2: UNKNOWN LIGAND

MacromoleculeName: UNKNOWN LIGAND / type: ligand / ID: 2 / Number of copies: 12 / Formula: UNL
Molecular weightTheoretical: 365.449 Da
Chemical component information


ChemComp, No image

ChemComp-UNL:
Unknown ligand

-
Macromolecule #3: (3,4-dihydroisoquinolin-2(1H)-yl)[2-(4-methoxyanilino)-1,3-thiazo...

MacromoleculeName: (3,4-dihydroisoquinolin-2(1H)-yl)[2-(4-methoxyanilino)-1,3-thiazol-4-yl]methanone
type: ligand / ID: 3 / Number of copies: 4 / Formula: A1CCX
Molecular weightTheoretical: 365.449 Da

-
Experimental details

-
Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

-
Sample preparation

BufferpH: 8
VitrificationCryogen name: ETHANE

-
Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Digitization - Dimensions - Width: 3838 pixel / Digitization - Dimensions - Height: 3710 pixel / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 130000
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

+
Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER
Final reconstructionApplied symmetry - Point group: C4 (4 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 15296
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more