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- EMDB-7133: Human TRPM4 ion channel in lipid nanodiscs in a calcium-bound state -

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Basic information

Entry
Database: EMDB / ID: EMD-7133
TitleHuman TRPM4 ion channel in lipid nanodiscs in a calcium-bound state
Map dataSharpened map of human TRPM4 ion channel in lipid nanodisc with 5 mM CaCl2. This reconstruction is of the entire molecule with C4 symmetry.
Sample
  • Complex: Human TRPM4 ion channel
    • Protein or peptide: Transient receptor potential cation channel subfamily M member 4
  • Ligand: CALCIUM IONCalcium
  • Ligand: CHOLESTEROL HEMISUCCINATE
KeywordsTRPM4 / TRPM channel / TRP channel / MEMBRANE PROTEIN
Function / homology
Function and homology information


positive regulation of atrial cardiac muscle cell action potential / positive regulation of regulation of vascular associated smooth muscle cell membrane depolarization / sodium channel complex / regulation of T cell cytokine production / membrane depolarization during AV node cell action potential / membrane depolarization during bundle of His cell action potential / membrane depolarization during Purkinje myocyte cell action potential / negative regulation of bone mineralization / ligand-gated calcium channel activity / sodium ion import across plasma membrane ...positive regulation of atrial cardiac muscle cell action potential / positive regulation of regulation of vascular associated smooth muscle cell membrane depolarization / sodium channel complex / regulation of T cell cytokine production / membrane depolarization during AV node cell action potential / membrane depolarization during bundle of His cell action potential / membrane depolarization during Purkinje myocyte cell action potential / negative regulation of bone mineralization / ligand-gated calcium channel activity / sodium ion import across plasma membrane / regulation of ventricular cardiac muscle cell action potential / sodium channel activity / calcium-activated cation channel activity / inorganic cation transmembrane transport / TRP channels / dendritic cell chemotaxis / cellular response to ATP / positive regulation of heart rate / regulation of heart rate by cardiac conduction / positive regulation of insulin secretion involved in cellular response to glucose stimulus / protein sumoylation / positive regulation of fat cell differentiation / negative regulation of osteoblast differentiation / positive regulation of vasoconstriction / positive regulation of adipose tissue development / calcium-mediated signaling / calcium ion transmembrane transport / Sensory perception of sweet, bitter, and umami (glutamate) taste / positive regulation of canonical Wnt signaling pathway / positive regulation of cytosolic calcium ion concentration / protein homotetramerization / adaptive immune response / calmodulin binding / neuronal cell body / calcium ion binding / positive regulation of cell population proliferation / Golgi apparatus / endoplasmic reticulum / nucleoplasm / ATP binding / membrane / identical protein binding / plasma membrane / cytosol
Similarity search - Function
TRPM, SLOG domain / SLOG in TRPM / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
Transient receptor potential cation channel subfamily M member 4
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsAutzen HE / Myasnikov AG
Funding support United States, Denmark, 5 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM098672 United States
National Institutes of Health/Office of the DirectorS10OD020054 United States
National Institutes of Health/Office of the DirectorS10OD021741 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R01NS047723 United States
Danish Council of Independent ResearchDFF-5051-00085 Denmark
CitationJournal: Science / Year: 2018
Title: Structure of the human TRPM4 ion channel in a lipid nanodisc.
Authors: Henriette E Autzen / Alexander G Myasnikov / Melody G Campbell / Daniel Asarnow / David Julius / Yifan Cheng /
Abstract: Transient receptor potential (TRP) melastatin 4 (TRPM4) is a widely expressed cation channel associated with a variety of cardiovascular disorders. TRPM4 is activated by increased intracellular ...Transient receptor potential (TRP) melastatin 4 (TRPM4) is a widely expressed cation channel associated with a variety of cardiovascular disorders. TRPM4 is activated by increased intracellular calcium in a voltage-dependent manner but, unlike many other TRP channels, is permeable to monovalent cations only. Here we present two structures of full-length human TRPM4 embedded in lipid nanodiscs at ~3-angstrom resolution, as determined by single-particle cryo-electron microscopy. These structures, with and without calcium bound, reveal a general architecture for this major subfamily of TRP channels and a well-defined calcium-binding site within the intracellular side of the S1-S4 domain. The structures correspond to two distinct closed states. Calcium binding induces conformational changes that likely prime the channel for voltage-dependent opening.
History
DepositionNov 28, 2017-
Header (metadata) releaseDec 20, 2017-
Map releaseDec 20, 2017-
UpdateMar 13, 2024-
Current statusMar 13, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 4
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 4
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6bqv
  • Surface level: 4
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_7133.png

Downloads & links

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Map

FileDownload / File: emd_7133.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpened map of human TRPM4 ion channel in lipid nanodisc with 5 mM CaCl2. This reconstruction is of the entire molecule with C4 symmetry.
Voxel sizeX=Y=Z: 1.046 Å
Density
Contour LevelBy AUTHOR: 4.0 / Movie #1: 4
Minimum - Maximum-30.481424000000001 - 47.155777
Average (Standard dev.)0.000000009518469 (±1.0000075)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 334.72 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0461.0461.046
M x/y/z320320320
origin x/y/z0.0000.0000.000
length x/y/z334.720334.720334.720
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS320320320
D min/max/mean-30.48147.1560.000

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Supplemental data

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Additional map: Unsharpened map of human TRPM4 ion channel in...

Fileemd_7133_additional_1.map
AnnotationUnsharpened map of human TRPM4 ion channel in lipid nanodisc with 5 mM CaCl2. This reconstruction is of the entire molecule with C4 symmetry.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: Sharpened map of human TRPM4 ion channel in...

Fileemd_7133_additional_2.map
AnnotationSharpened map of human TRPM4 ion channel in lipid nanodisc with 5 mM CaCl2. This reconstruction is focused on transmembrane domain, central coiled-coil domain, and MHR4 domain. C4 symmetry is applied.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: Sharpened map of human TRPM4 ion channel in...

Fileemd_7133_additional_3.map
AnnotationSharpened map of human TRPM4 ion channel in lipid nanodisc with 5 mM CaCl2. This reconstruction is focused on monomeric soluble domain without symmetry.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Human TRPM4 ion channel in lipid nanodiscs in...

Fileemd_7133_half_map_1.map
AnnotationHuman TRPM4 ion channel in lipid nanodiscs in a calcium-bound state, half map #1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map #2 of human TRPM4 ion channel...

Fileemd_7133_half_map_2.map
AnnotationHalf map #2 of human TRPM4 ion channel in lipid nanodisc with 5 mM CaCl2. This reconstruction is of the entire molecule with C4 symmetry.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Human TRPM4 ion channel

EntireName: Human TRPM4 ion channel
Components
  • Complex: Human TRPM4 ion channel
    • Protein or peptide: Transient receptor potential cation channel subfamily M member 4
  • Ligand: CALCIUM IONCalcium
  • Ligand: CHOLESTEROL HEMISUCCINATE

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Supramolecule #1: Human TRPM4 ion channel

SupramoleculeName: Human TRPM4 ion channel / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Details: Human TRPM4 ion channel in lipid nanodiscs in a calcium-bound state
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 134.6 KDa

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Macromolecule #1: Transient receptor potential cation channel subfamily M member 4

MacromoleculeName: Transient receptor potential cation channel subfamily M member 4
type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 134.770734 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: SGRSGVVPEK EQSWIPKIFK KKTCTTFIVD STDPGGTLCQ CGRPRTAHPA VAMEDAFGAA VVTVWDSDAH TTEKPTDAYG ELDFTGAGR KHSNFLRLSD RTDPAAVYSL VTRTWGFRAP NLVVSVLGGS GGPVLQTWLQ DLLRRGLVRA AQSTGAWIVT G GLHTGIGR ...String:
SGRSGVVPEK EQSWIPKIFK KKTCTTFIVD STDPGGTLCQ CGRPRTAHPA VAMEDAFGAA VVTVWDSDAH TTEKPTDAYG ELDFTGAGR KHSNFLRLSD RTDPAAVYSL VTRTWGFRAP NLVVSVLGGS GGPVLQTWLQ DLLRRGLVRA AQSTGAWIVT G GLHTGIGR HVGVAVRDHQ MASTGGTKVV AMGVAPWGVV RNRDTLINPK GSFPARYRWR GDPEDGVQFP LDYNYSAFFL VD DGTHGCL GGENRFRLRL ESYISQQKTG VGGTGIDIPV LLLLIDGDEK MLTRIENATQ AQLPCLLVAG SGGAADCLAE TLE DTLAPG SGGARQGEAR DRIRRFFPKG DLEVLQAQVE RIMTRKELLT VYSSEDGSEE FETIVLKALV KACGSSEASA YLDE LRLAV AWNRVDIAQS ELFRGDIQWR SFHLEASLMD ALLNDRPEFV RLLISHGLSL GHFLTPMRLA QLYSAAPSNS LIRNL LDQA SHSAGTKAPA LKGGAAELRP PDVGHVLRML LGKMCAPRYP SGGAWDPHPG QGFGESMYLL SDKATSPLSL DAGLGQ APW SDLLLWALLL NRAQMAMYFW EMGSNAVSSA LGACLLLRVM ARLEPDAEEA ARRKDLAFKF EGMGVDLFGE CYRSSEV RA ARLLLRRCPL WGDATCLQLA MQADARAFFA QDGVQSLLTQ KWWGDMASTT PIWALVLAFF CPPLIYTRLI TFRKSEEE P TREELEFDMD SVINGEGPVG TADPAEKTPL GVPRQSGRPG CCGGRCGGRR CLRRWFHFWG APVTIFMGNV VSYLLFLLL FSRVLLVDFQ PAPPGSLELL LYFWAFTLLC EELRQGLSGG GGSLASGGPG PGHASLSQRL RLYLADSWNQ CDLVALTCFL LGVGCRLTP GLYHLGRTVL CIDFMVFTVR LLHIFTVNKQ LGPKIVIVSK MMKDVFFFLF FLGVWLVAYG VATEGLLRPR D SDFPSILR RVFYRPYLQI FGQIPQEDMD VALMEHSNCS SEPGFWAHPP GAQAGTCVSQ YANWLVVLLL VIFLLVANIL LV NLLIAMF SYTFGKVQGN SDLYWKAQRY RLIREFHSRP ALAPPFIVIS HLRLLLRQLC RRPRSPQPSS PALEHFRVYL SKE AERKLL TWESVHKENF LLARARDKRE SDSERLKRTS QKVDLALKQL GHIREYEQRL KVLEREVQQC SRVLGWVAEA LSRS ALLPP GGPPPPDLPG SKD

UniProtKB: Transient receptor potential cation channel subfamily M member 4

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Macromolecule #2: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 2 / Number of copies: 4 / Formula: CA
Molecular weightTheoretical: 40.078 Da

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Macromolecule #3: CHOLESTEROL HEMISUCCINATE

MacromoleculeName: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 3 / Number of copies: 12 / Formula: Y01
Molecular weightTheoretical: 486.726 Da
Chemical component information

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

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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

Concentration2.2 mg/mL
BufferpH: 7.4
Component:
ConcentrationFormulaName
50.0 mMC8H18N2O4S4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), pH 7.4
150.0 mMNaClSodium chloridesodium chloride
5.0 mMCaCl2calcium chloride
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 200 / Support film - Material: CARBON / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 283 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.5 µm / Nominal magnification: 22500
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Number grids imaged: 1 / Number real images: 2954 / Average exposure time: 12.0 sec. / Average electron dose: 62.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 829078
Startup modelType of model: OTHER / Details: cryoSPARC ab initio model
Initial angle assignmentType: COMMON LINE / Software - Name: cryoSPARC
Final angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: RELION
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C4 (4 fold cyclic) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 2.1) / Number images used: 45346
DetailsK2 camera operating in super-resolution counting mode

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Atomic model buiding 1

RefinementProtocol: AB INITIO MODEL
Output model

PDB-6bqv:
Human TRPM4 ion channel in lipid nanodiscs in a calcium-bound state

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