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- EMDB-30847: Structure of a human NHE1-CHP1 complex under pH 6.5 -

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Entry
Database: EMDB / ID: EMD-30847
TitleStructure of a human NHE1-CHP1 complex under pH 6.5
Map data
Sample
  • Complex: Human NHE1-CHP1 complex under pH 6.5
    • Complex: Sodium/protein exchanger 1 (NHE1)
      • Protein or peptide: Sodium/hydrogen exchanger 1
    • Complex: Calcineurin B homologous protein 1 (CHP1)
      • Protein or peptide: Calcineurin B homologous protein 1
  • Ligand: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine
KeywordsTransporter / MEMBRANE PROTEIN
Function / homology
Function and homology information


positive regulation of sodium:proton antiporter activity / sodium:proton antiporter activity involved in regulation of cardiac muscle cell membrane potential / cation-transporting ATPase complex / Sodium/Proton exchangers / negative regulation of phosphatase activity / regulation of the force of heart contraction by cardiac conduction / transporter complex / positive regulation of calcium:sodium antiporter activity / positive regulation of protein glycosylation / Hyaluronan uptake and degradation ...positive regulation of sodium:proton antiporter activity / sodium:proton antiporter activity involved in regulation of cardiac muscle cell membrane potential / cation-transporting ATPase complex / Sodium/Proton exchangers / negative regulation of phosphatase activity / regulation of the force of heart contraction by cardiac conduction / transporter complex / positive regulation of calcium:sodium antiporter activity / positive regulation of protein glycosylation / Hyaluronan uptake and degradation / membrane docking / regulation of cardiac muscle cell membrane potential / potassium:proton antiporter activity / cellular response to electrical stimulus / positive regulation of phospholipid biosynthetic process / negative regulation of protein autophosphorylation / sodium:proton antiporter activity / positive regulation of action potential / positive regulation of protein transport / sodium ion export across plasma membrane / maintenance of cell polarity / regulation of pH / cellular response to acidic pH / positive regulation of calcineurin-NFAT signaling cascade / cardiac muscle cell differentiation / sodium ion import across plasma membrane / membrane organization / intracellular sodium ion homeostasis / protein phosphatase 2B binding / ion binding / microtubule bundle formation / regulation of stress fiber assembly / cardiac muscle cell contraction / response to acidic pH / regulation of cardiac muscle contraction by calcium ion signaling / positive regulation of mitochondrial membrane permeability / cellular response to cold / negative regulation of calcineurin-NFAT signaling cascade / cellular response to antibiotic / regulation of focal adhesion assembly / negative regulation of protein import into nucleus / small GTPase-mediated signal transduction / negative regulation of NF-kappaB transcription factor activity / protein kinase inhibitor activity / positive regulation of cardiac muscle hypertrophy / positive regulation of the force of heart contraction / positive regulation of protein targeting to membrane / endoplasmic reticulum-Golgi intermediate compartment / intercalated disc / potassium channel regulator activity / cytoplasmic microtubule organization / monoatomic ion transport / negative regulation of protein ubiquitination / transport vesicle / potassium ion transmembrane transport / phosphatidylinositol-4,5-bisphosphate binding / T-tubule / cellular response to epinephrine stimulus / response to muscle stretch / proton transmembrane transport / protein export from nucleus / negative regulation of protein phosphorylation / stem cell differentiation / regulation of intracellular pH / phospholipid binding / negative regulation of protein kinase activity / potassium ion transport / kinase binding / cellular response to mechanical stimulus / cellular response to insulin stimulus / calcium-dependent protein binding / microtubule cytoskeleton / cell migration / protein-macromolecule adaptor activity / protein complex oligomerization / lamellipodium / cellular response to hypoxia / microtubule binding / positive regulation of cell growth / basolateral plasma membrane / membrane fusion / molecular adaptor activity / protein stabilization / calmodulin binding / positive regulation of apoptotic process / membrane raft / apical plasma membrane / Golgi membrane / focal adhesion / calcium ion binding / negative regulation of apoptotic process / perinuclear region of cytoplasm / cell surface / endoplasmic reticulum / positive regulation of transcription by RNA polymerase II / mitochondrion / extracellular exosome / nucleoplasm / membrane / identical protein binding
Similarity search - Function
Sodium/hydrogen exchanger 1-like / Sodium/hydrogen exchanger, regulatory region / Regulatory region of Na+/H+ exchanger NHE binds to calmodulin / Na+/H+ exchanger / Cation/H+ exchanger, CPA1 family / Cation/H+ exchanger / Sodium/hydrogen exchanger family / EF-hand domain pair / EF-hand, calcium binding motif / EF-hand calcium-binding domain profile. ...Sodium/hydrogen exchanger 1-like / Sodium/hydrogen exchanger, regulatory region / Regulatory region of Na+/H+ exchanger NHE binds to calmodulin / Na+/H+ exchanger / Cation/H+ exchanger, CPA1 family / Cation/H+ exchanger / Sodium/hydrogen exchanger family / EF-hand domain pair / EF-hand, calcium binding motif / EF-hand calcium-binding domain profile. / EF-hand domain / EF-hand domain pair
Similarity search - Domain/homology
Sodium/hydrogen exchanger 1 / Calcineurin B homologous protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsDong Y / Gao Y / Li B / Zhang XC / Zhao Y
CitationJournal: Nat Commun / Year: 2021
Title: Structure and mechanism of the human NHE1-CHP1 complex.
Authors: Yanli Dong / Yiwei Gao / Alina Ilie / DuSik Kim / Annie Boucher / Bin Li / Xuejun C Zhang / John Orlowski / Yan Zhao /
Abstract: Sodium/proton exchanger 1 (NHE1) is an electroneutral secondary active transporter present on the plasma membrane of most mammalian cells and plays critical roles in regulating intracellular pH and ...Sodium/proton exchanger 1 (NHE1) is an electroneutral secondary active transporter present on the plasma membrane of most mammalian cells and plays critical roles in regulating intracellular pH and volume homeostasis. Calcineurin B-homologous protein 1 (CHP1) is an obligate binding partner that promotes NHE1 biosynthetic maturation, cell surface expression and pH-sensitivity. Dysfunctions of either protein are associated with neurological disorders. Here, we elucidate structures of the human NHE1-CHP1 complex in both inward- and inhibitor (cariporide)-bound outward-facing conformations. We find that NHE1 assembles as a symmetrical homodimer, with each subunit undergoing an elevator-like conformational change during cation exchange. The cryo-EM map reveals the binding site for the NHE1 inhibitor cariporide, illustrating how inhibitors block transport activity. The CHP1 molecule differentially associates with these two conformational states of each NHE1 monomer, and this association difference probably underlies the regulation of NHE1 pH-sensitivity by CHP1.
History
DepositionJan 3, 2021-
Header (metadata) releaseJun 23, 2021-
Map releaseJun 23, 2021-
UpdateMar 27, 2024-
Current statusMar 27, 2024Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.045
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.045
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7dsv
  • Surface level: 0.045
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7dsv
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_30847.png

Downloads & links

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Map

FileDownload / File: emd_30847.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1 Å
Density
Contour LevelBy AUTHOR: 0.045 / Movie #1: 0.045
Minimum - Maximum-0.2149519 - 0.3352891
Average (Standard dev.)0.00021320212 (±0.007281356)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 256.0 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z111
M x/y/z256256256
origin x/y/z0.0000.0000.000
length x/y/z256.000256.000256.000
α/β/γ90.00090.00090.000
start NX/NY/NZ192139186
NX/NY/NZ211274246
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS256256256
D min/max/mean-0.2150.3350.000

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Supplemental data

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Additional map: #1

Fileemd_30847_additional_1.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 : Human NHE1-CHP1 complex under pH 6.5

EntireName: Human NHE1-CHP1 complex under pH 6.5
Components
  • Complex: Human NHE1-CHP1 complex under pH 6.5
    • Complex: Sodium/protein exchanger 1 (NHE1)
      • Protein or peptide: Sodium/hydrogen exchanger 1
    • Complex: Calcineurin B homologous protein 1 (CHP1)
      • Protein or peptide: Calcineurin B homologous protein 1
  • Ligand: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine

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Supramolecule #1: Human NHE1-CHP1 complex under pH 6.5

SupramoleculeName: Human NHE1-CHP1 complex under pH 6.5 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Details: CHP1 in this map was locally refined using symmetry expansion to improve resolution.
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 230 KDa

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Supramolecule #2: Sodium/protein exchanger 1 (NHE1)

SupramoleculeName: Sodium/protein exchanger 1 (NHE1) / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 182 KDa

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Supramolecule #3: Calcineurin B homologous protein 1 (CHP1)

SupramoleculeName: Calcineurin B homologous protein 1 (CHP1) / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2

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Macromolecule #1: Sodium/hydrogen exchanger 1

MacromoleculeName: Sodium/hydrogen exchanger 1 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 52.893367 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: KAFPVLGIDY THVRTPFEIS LWILLACLMK IGFHVIPTIS SIVPESCLLI VVGLLVGGLI KGVGETPPFL QSDVFFLFLL PPIILDAGY FLPLRQFTEN LGTILIFAVV GTLWNAFFLG GLMYAVCLVG GEQINNIGLL DNLLFGSIIS AVDPVAVLAV F EEIHINEL ...String:
KAFPVLGIDY THVRTPFEIS LWILLACLMK IGFHVIPTIS SIVPESCLLI VVGLLVGGLI KGVGETPPFL QSDVFFLFLL PPIILDAGY FLPLRQFTEN LGTILIFAVV GTLWNAFFLG GLMYAVCLVG GEQINNIGLL DNLLFGSIIS AVDPVAVLAV F EEIHINEL LHILVFGESL LNDAVTVVLY HLFEEFANYE HVGIVDIFLG FLSFFVVALG GVLVGVVYGV IAAFTSRFTS HI RVIEPLF VFLYSYMAYL SAELFHLSGI MALIASGVVM RPYVEANISH KSHTTIKYFL KMWSSVSETL IFIFLGVSTV AGS HHWNWT FVISTLLFCL IARVLGVLGL TWFINKFRIV KLTPKDQFII AYGGLRGAIA FSLGYLLDKK HFPMCDLFLT AIIT VIFFT VFVQGMTIRP LVDLLAVKKK QETKRSINEE IHTQFLDHLL TGIEDICGHY GHHHWKDKLN RFNKKYV

UniProtKB: Sodium/hydrogen exchanger 1

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Macromolecule #2: Calcineurin B homologous protein 1

MacromoleculeName: Calcineurin B homologous protein 1 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 21.36983 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
DEELEEIKKE TGFSHSQITR LYSRFTSLDK GENGTLSRED FQRIPELAIN PLGDRIINAF FPEGEDQVNF RGFMRTLAHF RPIEDNEKS KDVNGPEPLN SRSNKLHFAF RLYDLDKDEK ISRDELLQVL RMMVGVNISD EQLGSIADRT IQEADQDGDS A ASFTEFVK VLEKVDVEQK MSIRFLH

UniProtKB: Calcineurin B homologous protein 1

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Macromolecule #3: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine

MacromoleculeName: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine / type: ligand / ID: 3 / Number of copies: 16 / Formula: LBN
Molecular weightTheoretical: 760.076 Da
Chemical component information

ChemComp-LBN:
1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine / phospholipid*YM / POPC

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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

Concentration6 mg/mL
BufferpH: 6.5
GridModel: Quantifoil / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 60 sec. / Pretreatment - Atmosphere: OTHER
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK III
DetailsThe NHE1-CHP1 complex was reconstituted into lipid nanodiscs.

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.2 µm / Nominal magnification: 13000
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
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 / Digitization - Dimensions - Width: 3838 pixel / Digitization - Dimensions - Height: 3710 pixel / Digitization - Frames/image: 1-32 / Number grids imaged: 1 / Number real images: 2205 / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
In silico model: The insilico model was generated using Ab initio reconstruction in cryoSPARC.
Initial angle assignmentType: ANGULAR RECONSTITUTION / Software: (Name: RELION (ver. 3.1), cryoSPARC (ver. 2.15))
Final angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: RELION (ver. 3.1)
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1) / Number images used: 100503
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementProtocol: AB INITIO MODEL
Output model

PDB-7dsv:
Structure of a human NHE1-CHP1 complex under pH 6.5

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