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- EMDB-37718: Cryo-EM structure of the human TRPC1/C4 heteromer -

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Basic information

Entry
Database: EMDB / ID: EMD-37718
TitleCryo-EM structure of the human TRPC1/C4 heteromer
Map data
Sample
  • Complex: Structure of a TRP channel complex, apo state
    • Protein or peptide: Short transient receptor potential channel 1
    • Protein or peptide: Short transient receptor potential channel 4
  • Ligand: 2-(HEXADECANOYLOXY)-1-[(PHOSPHONOOXY)METHYL]ETHYL HEXADECANOATE
  • Ligand: ZINC ION
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: CALCIUM ION
Keywordstransient receptor potential / METAL TRANSPORT
Function / homology
Function and homology information


Role of second messengers in netrin-1 signaling / gamma-aminobutyric acid secretion / store-operated calcium channel activity / cation channel complex / melanin biosynthetic process / inositol 1,4,5 trisphosphate binding / calcium ion import / TRP channels / cortical cytoskeleton / oligodendrocyte differentiation ...Role of second messengers in netrin-1 signaling / gamma-aminobutyric acid secretion / store-operated calcium channel activity / cation channel complex / melanin biosynthetic process / inositol 1,4,5 trisphosphate binding / calcium ion import / TRP channels / cortical cytoskeleton / oligodendrocyte differentiation / regulation of cardiac conduction / regulation of cytosolic calcium ion concentration / monoatomic cation channel activity / Ion homeostasis / calcium channel complex / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / positive regulation of release of sequestered calcium ion into cytosol / beta-catenin binding / caveola / calcium channel activity / calcium ion transmembrane transport / response to calcium ion / calcium ion transport / ATPase binding / basolateral plasma membrane / transmembrane transporter binding / receptor complex / cadherin binding / signaling receptor binding / cell surface / plasma membrane
Similarity search - Function
Transient receptor potential channel, canonical 1 / Transient receptor potential channel, canonical 4 / Transient receptor ion channel domain / Transient receptor ion channel II / Transient receptor ion channel II / Transient receptor potential channel, canonical / Ankyrin repeat / Ankyrin repeats (3 copies) / Ankyrin repeat profile. / Ankyrin repeat region circular profile. ...Transient receptor potential channel, canonical 1 / Transient receptor potential channel, canonical 4 / Transient receptor ion channel domain / Transient receptor ion channel II / Transient receptor ion channel II / Transient receptor potential channel, canonical / 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
Short transient receptor potential channel 1 / Short transient receptor potential channel 4
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.04 Å
AuthorsWon J / Jeong H / Lee HH
Funding support Korea, Republic Of, 1 items
OrganizationGrant numberCountry
Other privateSSTF-BA2101-13 Korea, Republic Of
CitationJournal: Nat Struct Mol Biol / Year: 2025
Title: Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel.
Authors: Jongdae Won / Jinhyeong Kim / Jinsung Kim / Juyeon Ko / Christine Haewon Park / Byeongseok Jeong / Sang-Eun Lee / Hyeongseop Jeong / Sun-Hong Kim / Hyunwoo Park / Insuk So / Hyung Ho Lee /
Abstract: Transient receptor potential (TRP) ion channels have a crucial role as cellular sensors, mediating diverse physical and chemical stimuli. The formation of heteromeric structures expands the ...Transient receptor potential (TRP) ion channels have a crucial role as cellular sensors, mediating diverse physical and chemical stimuli. The formation of heteromeric structures expands the functionality of TRP channels; however, their molecular architecture remains largely unknown. Here we present the cryo-electron microscopy structures of the human TRPC1/TRPC4 heteromer in the apo and antagonist-bound states, both consisting of one TRPC1 subunit and three TRPC4 subunits. The heteromer structure reveals a distinct ion-conduction pathway, including an asymmetrically constricted selectivity filter and an asymmetric lower gate, primarily attributed to the incorporation of TRPC1. Through a structure-guided electrophysiological assay, we show that both the selectivity filter and the lower part of the S6 helix participate in deciding overall preference for permeating monovalent cations. Moreover, we reveal that the introduction of one lysine residue of TRPC1 into the tetrameric central cavity is enough to render one of the most important functional consequences of TRPC heteromerization: reduced calcium permeability. Our results establish a framework for addressing the structure-function relationship of the heteromeric TRP channels.
History
DepositionOct 10, 2023-
Header (metadata) releaseOct 16, 2024-
Map releaseOct 16, 2024-
UpdateMar 5, 2025-
Current statusMar 5, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_37718.png

Downloads & links

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Map

FileDownload / File: emd_37718.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.82 Å/pix.
x 360 pix.
= 295.2 Å		0.82 Å/pix.
x 360 pix.
= 295.2 Å		0.82 Å/pix.
x 360 pix.
= 295.2 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.82 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.12
Minimum - Maximum-0.9045479 - 1.2726792
Average (Standard dev.)0.0009772999 (±0.033380087)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 295.2 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_37718_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_37718_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Structure of a TRP channel complex, apo state

EntireName: Structure of a TRP channel complex, apo state
Components
  • Complex: Structure of a TRP channel complex, apo state
    • Protein or peptide: Short transient receptor potential channel 1
    • Protein or peptide: Short transient receptor potential channel 4
  • Ligand: 2-(HEXADECANOYLOXY)-1-[(PHOSPHONOOXY)METHYL]ETHYL HEXADECANOATE
  • Ligand: ZINC ION
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: CALCIUM ION

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Supramolecule #1: Structure of a TRP channel complex, apo state

SupramoleculeName: Structure of a TRP channel complex, apo state / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Short transient receptor potential channel 1

MacromoleculeName: Short transient receptor potential channel 1 / type: protein_or_peptide / ID: 1 / Details: GPVD (1-4) linker / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 91.688164 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: GPVDMMAALY PSTDLSGASS SSLPSSPSSS SPNEVMALKD VREVKEENTL NEKLFLLACD KGDYYMVKKI LEENSSGDLN INCVDVLGR NAVTITIENE NLDILQLLLD YGCQSADALL VAIDSEVVGA VDILLNHRPK RSSRPTIVKL MERIQNPEYS T TMDVAPVI ...String:
GPVDMMAALY PSTDLSGASS SSLPSSPSSS SPNEVMALKD VREVKEENTL NEKLFLLACD KGDYYMVKKI LEENSSGDLN INCVDVLGR NAVTITIENE NLDILQLLLD YGCQSADALL VAIDSEVVGA VDILLNHRPK RSSRPTIVKL MERIQNPEYS T TMDVAPVI LAAHRNNYEI LTMLLKQDVS LPKPHAVGCE CTLCSAKNKK DSLRHSRFRL DIYRCLASPA LIMLTEEDPI LR AFELSAD LKELSLVEVE FRNDYEELAR QCKMFAKDLL AQARNSRELE VILNHTSSDE PLDKRGLLEE RMNLSRLKLA IKY NQKEFV SQSNCQQFLN TVWFGQMSGY RRKPTCKKIM TVLTVGIFWP VLSLCYLIAP KSQFGRIIHT PFMKFIIHGA SYFT FLLLL NLYSLVYNED KKNTMGPALE RIDYLLILWI IGMIWSDIKR LWYEGLEDFL EESRNQLSFV MNSLYLATFA LKVVA HNKF HDFADRKDWD AFHPTLVAEG LFAFANVLSY LRLFFMYTTS SILGPLQISM GQMLQDFGKF LGMFLLVLFS FTIGLT QLY DKGYTSKEQK DCVGIFCEQQ SNDTFHSFIG TCFALFWYIF SLAHVAIFVT RFSYGEELQS FVGAVIVGTY NVVVVIV LT KLLVAMLHKS FQLIANHEDK EWKFARAKLW LSYFDDKCTL PPPFNIIPSP KTICYMISSL SKWICSHTSK GKVKRQNS L KEWRNLKQKR DENYQKVMCC LVHRYLTSMR QKMQSTDQAT VENLNELRQD LSKFRNEIRD LLGFRTSKYA MFYPRN

UniProtKB: Short transient receptor potential channel 1

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Macromolecule #2: Short transient receptor potential channel 4

MacromoleculeName: Short transient receptor potential channel 4 / type: protein_or_peptide / ID: 2 / Details: SRASTVPRARDPPVATLEVLFQ (894-915), linker / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 105.157977 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAQFYYKRNV NAPYRDRIPL RIVRAESELS PSEKAYLNAV EKGDYASVKK SLEEAEIYFK ININCIDPLG RTALLIAIEN ENLELIELL LSFNVYVGDA LLHAIRKEVV GAVELLLNHK KPSGEKQVPP ILLDKQFSEF TPDITPIILA AHTNNYEIIK L LVQKGVSV ...String:
MAQFYYKRNV NAPYRDRIPL RIVRAESELS PSEKAYLNAV EKGDYASVKK SLEEAEIYFK ININCIDPLG RTALLIAIEN ENLELIELL LSFNVYVGDA LLHAIRKEVV GAVELLLNHK KPSGEKQVPP ILLDKQFSEF TPDITPIILA AHTNNYEIIK L LVQKGVSV PRPHEVRCNC VECVSSSDVD SLRHSRSRLN IYKALASPSL IALSSEDPFL TAFQLSWELQ ELSKVENEFK SE YEELSRQ CKQFAKDLLD QTRSSRELEI ILNYRDDNSL IEEQSGNDLA RLKLAIKYRQ KEFVAQPNCQ QLLASRWYDE FPG WRRRHW AVKMVTCFII GLLFPVFSVC YLIAPKSPLG LFIRKPFIKF ICHTASYLTF LFLLLLASQH IDRSDLNRQG PPPT IVEWM ILPWVLGFIW GEIKQMWDGG LQDYIHDWWN LMDFVMNSLY LATISLKIVA FVKYSALNPR ESWDMWHPTL VAEAL FAIA NIFSSLRLIS LFTANSHLGP LQISLGRMLL DILKFLFIYC LVLLAFANGL NQLYFYYEET KGLTCKGIRC EKQNNA FST LFETLQSLFW SIFGLINLYV TNVKAQHEFT EFVGATMFGT YNVISLVVLL NMLIAMMNNS YQLIADHADI EWKFART KL WMSYFEEGGT LPTPFNVIPS PKSLWYLIKW IWTHLCKKKM RRKPESFGTI GRRAADNLRR HHQYQEVMRN LVKRYVAA M IRDAKTEEGL TEENFKELKQ DISSFRFEVL GLLRGSKLST IQSANASKES SNSADSDEKS DSEEEVARQQ AAGPLERNI QLESRGLASR GDLSIPGLSE QCVLVDHRER NTDTLGLQVG KRVCPFKSEK VVVEDTVPII PKEKHAKEED SSIDYDLNLP DTVTHEDYV TTRLSRASTV PRARDPPVAT LEVLFQ

UniProtKB: Short transient receptor potential channel 4

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Macromolecule #3: 2-(HEXADECANOYLOXY)-1-[(PHOSPHONOOXY)METHYL]ETHYL HEXADECANOATE

MacromoleculeName: 2-(HEXADECANOYLOXY)-1-[(PHOSPHONOOXY)METHYL]ETHYL HEXADECANOATE
type: ligand / ID: 3 / Number of copies: 4 / Formula: LPP
Molecular weightTheoretical: 648.891 Da
Chemical component information

ChemComp-LPP:
2-(HEXADECANOYLOXY)-1-[(PHOSPHONOOXY)METHYL]ETHYL HEXADECANOATE / phospholipid*YM

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Macromolecule #4: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 4 / Number of copies: 4 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #5: CHOLESTEROL HEMISUCCINATE

MacromoleculeName: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 5 / Number of copies: 3 / Formula: Y01
Molecular weightTheoretical: 486.726 Da
Chemical component information

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

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Macromolecule #6: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 6 / Number of copies: 3 / Formula: CA
Molecular weightTheoretical: 40.078 Da

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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

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 64.8 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

5z96


Details: AlphaFold-TRPC1 was also used
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.04 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 65997
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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