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- EMDB-30849: Structure of a human NHE1-CHP1 complex under pH 7.5, bound by car... -

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Basic information

Entry
Database: EMDB / ID: EMD-30849
TitleStructure of a human NHE1-CHP1 complex under pH 7.5, bound by cariporide
Map data
Sample
  • Complex: Human NHE1-CHP1 complex under pH 7.5, bound by cariporide
    • Complex: Sodium/protein exchanger 1 (NHE1) under pH 7.5, bound by cariporide
      • Protein or peptide: Calcineurin B homologous protein 1
    • Complex: Calcineurin B homologous protein 1 (CHP1) under pH 7.5
      • Protein or peptide: Sodium/hydrogen exchanger 1
  • Ligand: (1S)-2-{[{[(2R)-2,3-DIHYDROXYPROPYL]OXY}(HYDROXY)PHOSPHORYL]OXY}-1-[(PALMITOYLOXY)METHYL]ETHYL STEARATE
  • Ligand: N-[bis(azanyl)methylidene]-3-methylsulfonyl-4-propan-2-yl-benzamide
KeywordsTransporter / MEMBRANE PROTEIN
Function / homology
Function and homology information


negative regulation of phosphatase activity / positive regulation of sodium:proton antiporter activity / positive regulation of mitochondrial membrane permeability / regulation of the force of heart contraction by cardiac conduction / Sodium/Proton exchangers / membrane docking / negative regulation of protein autophosphorylation / Hyaluronan degradation / positive regulation of protein transport / cation-transporting ATPase complex ...negative regulation of phosphatase activity / positive regulation of sodium:proton antiporter activity / positive regulation of mitochondrial membrane permeability / regulation of the force of heart contraction by cardiac conduction / Sodium/Proton exchangers / membrane docking / negative regulation of protein autophosphorylation / Hyaluronan degradation / positive regulation of protein transport / cation-transporting ATPase complex / cellular response to electrical stimulus / positive regulation of phospholipid biosynthetic process / transporter complex / regulation of cardiac muscle cell membrane potential / potassium:proton antiporter activity / regulation of pH / positive regulation of action potential / positive regulation of glycoprotein biosynthetic process / hyaluronan catabolic process / maintenance of cell polarity / sodium:proton antiporter activity / positive regulation of calcineurin-NFAT signaling cascade / membrane organization / cellular response to cold / sodium ion export across plasma membrane / microtubule bundle formation / protein phosphatase 2B binding / regulation of stress fiber assembly / intracellular sodium ion homeostasis / negative regulation of protein import into nucleus / negative regulation of calcineurin-NFAT signaling cascade / response to acidic pH / sodium ion import across plasma membrane / regulation of focal adhesion assembly / regulation of cardiac muscle contraction by calcium ion signaling / cellular response to antibiotic / cardiac muscle cell contraction / positive regulation of cardiac muscle hypertrophy / small GTPase-mediated signal transduction / positive regulation of the force of heart contraction / endoplasmic reticulum-Golgi intermediate compartment / negative regulation of protein phosphorylation / protein kinase inhibitor activity / response to muscle stretch / protein complex oligomerization / intercalated disc / potassium channel regulator activity / positive regulation of protein targeting to membrane / potassium ion transport / protein export from nucleus / transport vesicle / negative regulation of protein kinase activity / cellular response to acidic pH / cytoplasmic microtubule organization / phosphatidylinositol-4,5-bisphosphate binding / negative regulation of protein ubiquitination / cellular response to epinephrine stimulus / proton transmembrane transport / potassium ion transmembrane transport / T-tubule / regulation of intracellular pH / sodium ion transmembrane transport / cellular response to mechanical stimulus / phospholipid binding / kinase binding / calcium-dependent protein binding / microtubule cytoskeleton / cellular response to insulin stimulus / cell migration / positive regulation of cell growth / lamellipodium / cellular response to hypoxia / microtubule binding / molecular adaptor activity / basolateral plasma membrane / membrane fusion / cell differentiation / protein-macromolecule adaptor activity / calmodulin binding / protein stabilization / apical plasma membrane / positive regulation of apoptotic process / membrane raft / 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 / membrane / identical protein binding / nucleus / plasma membrane / cytoplasm
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, transmembrane / EF-hand domain pair / EF-hand, calcium binding motif ...: / 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, transmembrane / 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: 3.5 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: 0.4
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.4
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7dsx
  • Surface level: 0.4
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_30849.png

Downloads & links

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Map

FileDownload / File: emd_30849.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.04 Å/pix.
x 256 pix.
= 266.24 Å		1.04 Å/pix.
x 256 pix.
= 266.24 Å		1.04 Å/pix.
x 256 pix.
= 266.24 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.04 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.4 / Movie #1: 0.4
Minimum - Maximum-1.8720708 - 2.9233146
Average (Standard dev.)0.0007913535 (±0.08707499)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 266.24 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.041.041.04
M x/y/z256256256
origin x/y/z0.0000.0000.000
length x/y/z266.240266.240266.240
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-1.8722.9230.001

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Supplemental data

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Sample components

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Entire : Human NHE1-CHP1 complex under pH 7.5, bound by cariporide

EntireName: Human NHE1-CHP1 complex under pH 7.5, bound by cariporide
Components
  • Complex: Human NHE1-CHP1 complex under pH 7.5, bound by cariporide
    • Complex: Sodium/protein exchanger 1 (NHE1) under pH 7.5, bound by cariporide
      • Protein or peptide: Calcineurin B homologous protein 1
    • Complex: Calcineurin B homologous protein 1 (CHP1) under pH 7.5
      • Protein or peptide: Sodium/hydrogen exchanger 1
  • Ligand: (1S)-2-{[{[(2R)-2,3-DIHYDROXYPROPYL]OXY}(HYDROXY)PHOSPHORYL]OXY}-1-[(PALMITOYLOXY)METHYL]ETHYL STEARATE
  • Ligand: N-[bis(azanyl)methylidene]-3-methylsulfonyl-4-propan-2-yl-benzamide

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Supramolecule #1: Human NHE1-CHP1 complex under pH 7.5, bound by cariporide

SupramoleculeName: Human NHE1-CHP1 complex under pH 7.5, bound by cariporide
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 230 KDa

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Supramolecule #2: Sodium/protein exchanger 1 (NHE1) under pH 7.5, bound by cariporide

SupramoleculeName: Sodium/protein exchanger 1 (NHE1) under pH 7.5, bound by cariporide
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) under pH 7.5

SupramoleculeName: Calcineurin B homologous protein 1 (CHP1) under pH 7.5
type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2

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Macromolecule #1: Calcineurin B homologous protein 1

MacromoleculeName: Calcineurin B homologous protein 1 / type: protein_or_peptide / ID: 1 / 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 #2: Sodium/hydrogen exchanger 1

MacromoleculeName: Sodium/hydrogen exchanger 1 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 57.100363 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: PRKAFPVLGI DYTHVRTPFE ISLWILLACL MKIGFHVIPT ISSIVPESCL LIVVGLLVGG LIKGVGETPP FLQSDVFFLF LLPPIILDA GYFLPLRQFT ENLGTILIFA VVGTLWNAFF LGGLMYAVCL VGGEQINNIG LLDNLLFGSI ISAVDPVAVL A VFEEIHIN ...String:
PRKAFPVLGI DYTHVRTPFE ISLWILLACL MKIGFHVIPT ISSIVPESCL LIVVGLLVGG LIKGVGETPP FLQSDVFFLF LLPPIILDA GYFLPLRQFT ENLGTILIFA VVGTLWNAFF LGGLMYAVCL VGGEQINNIG LLDNLLFGSI ISAVDPVAVL A VFEEIHIN ELLHILVFGE SLLNDAVTVV LYHLFEEFAN YEHVGIVDIF LGFLSFFVVA LGGVLVGVVY GVIAAFTSRF TS HIRVIEP LFVFLYSYMA YLSAELFHLS GIMALIASGV VMRPYVEANI SHKSHTTIKY FLKMWSSVSE TLIFIFLGVS TVA GSHHWN WTFVISTLLF CLIARVLGVL GLTWFINKFR IVKLTPKDQF IIAYGGLRGA IAFSLGYLLD KKHFPMCDLF LTAI ITVIF FTVFVQGMTI RPLVDLLAVK KKQETKRSIN EEIHTQFLDH LLTGIEDICG HYGHHHWKDK LNRFNKKYVK KCLIA GERS KEPQLIAFYH KMEMKQAIEL VESGG

UniProtKB: Sodium/hydrogen exchanger 1

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Macromolecule #3: (1S)-2-{[{[(2R)-2,3-DIHYDROXYPROPYL]OXY}(HYDROXY)PHOSPHORYL]OXY}-...

MacromoleculeName: (1S)-2-{[{[(2R)-2,3-DIHYDROXYPROPYL]OXY}(HYDROXY)PHOSPHORYL]OXY}-1-[(PALMITOYLOXY)METHYL]ETHYL STEARATE
type: ligand / ID: 3 / Number of copies: 6 / Formula: PGT
Molecular weightTheoretical: 751.023 Da
Chemical component information

ChemComp-PGT:
(1S)-2-{[{[(2R)-2,3-DIHYDROXYPROPYL]OXY}(HYDROXY)PHOSPHORYL]OXY}-1-[(PALMITOYLOXY)METHYL]ETHYL STEARATE / phospholipid*YM

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Macromolecule #4: N-[bis(azanyl)methylidene]-3-methylsulfonyl-4-propan-2-yl-benzamide

MacromoleculeName: N-[bis(azanyl)methylidene]-3-methylsulfonyl-4-propan-2-yl-benzamide
type: ligand / ID: 4 / Number of copies: 2 / Formula: HG0
Molecular weightTheoretical: 283.347 Da
Chemical component information

ChemComp-HG0:
N-[bis(azanyl)methylidene]-3-methylsulfonyl-4-propan-2-yl-benzamide / inhibitor*YM

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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: 7.5
GridModel: Quantifoil / Material: COPPER / Mesh: 200 / Support film - Material: CARBON / Support film - topology: HOLEY
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 TITAN 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: SUPER-RESOLUTION / Digitization - Dimensions - Width: 3838 pixel / Digitization - Dimensions - Height: 3710 pixel / Digitization - Frames/image: 1-32 / Number grids imaged: 1 / Number real images: 3855 / 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 / Cs: 2.7 mm / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.2 µm / Nominal magnification: 13000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / 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.
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 2.15) / Number images used: 61460
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)
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementProtocol: AB INITIO MODEL
Output model

PDB-7dsx:
Structure of a human NHE1-CHP1 complex under pH 7.5, bound by cariporide

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