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- EMDB-36465: structure of human sodium-calciumexchanger NCX1 -

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Basic information

Entry
Database: EMDB / ID: EMD-36465
Titlestructure of human sodium-calciumexchanger NCX1
Map data
Sample
  • Complex: Human sodium/calcium exchenger 1(NCX1), monomer
    • Protein or peptide: Sodium/calcium exchanger 1
  • Ligand: 2-{4-[(2,5-difluorophenyl)methoxy]phenoxy}-5-ethoxyaniline
Keywordssodium/calcium exchanger / membrane protein / TRANSPORT PROTEIN
Function / homology
Function and homology information


relaxation of smooth muscle / vascular associated smooth muscle contraction / calcium ion export / regulation of cell communication by electrical coupling / calcium:sodium antiporter activity / membrane depolarization during cardiac muscle cell action potential / regulation of the force of heart contraction / sodium ion export across plasma membrane / negative regulation of protein serine/threonine kinase activity / sodium ion import across plasma membrane ...relaxation of smooth muscle / vascular associated smooth muscle contraction / calcium ion export / regulation of cell communication by electrical coupling / calcium:sodium antiporter activity / membrane depolarization during cardiac muscle cell action potential / regulation of the force of heart contraction / sodium ion export across plasma membrane / negative regulation of protein serine/threonine kinase activity / sodium ion import across plasma membrane / intracellular sodium ion homeostasis / calcium ion import / regulation of cardiac muscle contraction by calcium ion signaling / cardiac muscle cell development / calcium ion transport into cytosol / Sodium/Calcium exchangers / calcium ion transmembrane import into cytosol / relaxation of cardiac muscle / cell communication by electrical coupling involved in cardiac conduction / Reduction of cytosolic Ca++ levels / ankyrin binding / negative regulation of cytosolic calcium ion concentration / cellular response to caffeine / positive regulation of the force of heart contraction / intercalated disc / sodium ion transmembrane transport / calcium ion import across plasma membrane / regulation of cardiac conduction / calcium ion homeostasis / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / positive regulation of bone mineralization / monoatomic ion transport / cardiac muscle contraction / axon terminus / Ion homeostasis / T-tubule / cytoskeletal protein binding / response to muscle stretch / regulation of heart rate / muscle contraction / cell periphery / calcium ion transmembrane transport / sarcolemma / Z disc / cellular response to reactive oxygen species / intracellular calcium ion homeostasis / postsynapse / regulation of gene expression / transmembrane transporter binding / postsynaptic density / calmodulin binding / axon / neuronal cell body / synapse / calcium ion binding / dendrite / nucleoplasm / plasma membrane
Similarity search - Function
Sodium/calcium exchanger, isoform 1 / Sodium/calcium exchanger protein / Sodium/calcium exchanger domain, C-terminal extension / C-terminal extension of sodium/calcium exchanger domain / Na-Ca exchanger/integrin-beta4 / Calx-beta domain / Domains in Na-Ca exchangers and integrin-beta4 / NCX, central ion-binding domain superfamily / Sodium/calcium exchanger membrane region / Sodium/calcium exchanger protein ...Sodium/calcium exchanger, isoform 1 / Sodium/calcium exchanger protein / Sodium/calcium exchanger domain, C-terminal extension / C-terminal extension of sodium/calcium exchanger domain / Na-Ca exchanger/integrin-beta4 / Calx-beta domain / Domains in Na-Ca exchangers and integrin-beta4 / NCX, central ion-binding domain superfamily / Sodium/calcium exchanger membrane region / Sodium/calcium exchanger protein / CalX-like domain superfamily / DnaJ domain
Similarity search - Domain/homology
Sodium/calcium exchanger 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsDong Y / Zhao Y
Funding support China, 2 items
OrganizationGrant numberCountry
Chinese Academy of SciencesXDB37030304 China
National Natural Science Foundation of China (NSFC)92157102 China
CitationJournal: EMBO J / Year: 2024
Title: Structural insight into the allosteric inhibition of human sodium-calcium exchanger NCX1 by XIP and SEA0400.
Authors: Yanli Dong / Zhuoya Yu / Yue Li / Bo Huang / Qinru Bai / Yiwei Gao / Qihao Chen / Na Li / Lingli He / Yan Zhao /
Abstract: Sodium-calcium exchanger proteins influence calcium homeostasis in many cell types and participate in a wide range of physiological and pathological processes. Here, we elucidate the cryo-EM ...Sodium-calcium exchanger proteins influence calcium homeostasis in many cell types and participate in a wide range of physiological and pathological processes. Here, we elucidate the cryo-EM structure of the human Na/Ca exchanger NCX1.3 in the presence of a specific inhibitor, SEA0400. Conserved ion-coordinating residues are exposed on the cytoplasmic face of NCX1.3, indicating that the observed structure is stabilized in an inward-facing conformation. We show how regulatory calcium-binding domains (CBDs) assemble with the ion-translocation transmembrane domain (TMD). The exchanger-inhibitory peptide (XIP) is trapped within a groove between the TMD and CBD2 and predicted to clash with gating helices TMs at the outward-facing state, thus hindering conformational transition and promoting inactivation of the transporter. A bound SEA0400 molecule stiffens helix TM2ab and affects conformational rearrangements of TM2ab that are associated with the ion-exchange reaction, thus allosterically attenuating Ca-uptake activity of NCX1.3.
History
DepositionJun 9, 2023-
Header (metadata) releaseJan 3, 2024-
Map releaseJan 3, 2024-
UpdateJan 24, 2024-
Current statusJan 24, 2024Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_36465.png

Downloads & links

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Map

FileDownload / File: emd_36465.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.82 Å
Density
Contour LevelBy AUTHOR: 0.3
Minimum - Maximum-1.3272879 - 1.9273971
Average (Standard dev.)-0.0008691204 (±0.038704865)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 262.4 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_36465_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_36465_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 : Human sodium/calcium exchenger 1(NCX1), monomer

EntireName: Human sodium/calcium exchenger 1(NCX1), monomer
Components
  • Complex: Human sodium/calcium exchenger 1(NCX1), monomer
    • Protein or peptide: Sodium/calcium exchanger 1
  • Ligand: 2-{4-[(2,5-difluorophenyl)methoxy]phenoxy}-5-ethoxyaniline

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Supramolecule #1: Human sodium/calcium exchenger 1(NCX1), monomer

SupramoleculeName: Human sodium/calcium exchenger 1(NCX1), monomer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Sodium/calcium exchanger 1

MacromoleculeName: Sodium/calcium exchanger 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 104.794266 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MYNMRRLSLS PTFSMGFHLL VTVSLLFSHV DHVIAETEME GEGNETGECT GSYYCKKGVI LPIWEPQDPS FGDKIARATV YFVAMVYMF LGVSIIADRF MSSIEVITSQ EKEITIKKPN GETTKTTVRI WNETVSNLTL MALGSSAPEI LLSVIEVCGH N FTAGDLGP ...String:
MYNMRRLSLS PTFSMGFHLL VTVSLLFSHV DHVIAETEME GEGNETGECT GSYYCKKGVI LPIWEPQDPS FGDKIARATV YFVAMVYMF LGVSIIADRF MSSIEVITSQ EKEITIKKPN GETTKTTVRI WNETVSNLTL MALGSSAPEI LLSVIEVCGH N FTAGDLGP STIVGSAAFN MFIIIALCVY VVPDGETRKI KHLRVFFVTA AWSIFAYTWL YIILSVISPG VVEVWEGLLT FF FFPICVV FAWVADRRLL FYKYVYKRYR AGKQRGMIIE HEGDRPSSKT EIEMDGKVVN SHVENFLDGA LVLEVDERDQ DDE EARREM ARILKELKQK HPDKEIEQLI ELANYQVLSQ QQKSRAFYRI QATRLMTGAG NILKRHAADQ ARKAVSMHEV NTEV TENDP VSKIFFEQGT YQCLENCGTV ALTIIRRGGD LTNTVFVDFR TEDGTANAGS DYEFTEGTVV FKPGDTQKEI RVGII DDDI FEEDENFLVH LSNVKVSSEA SEDGILEANH VSTLACLGSP STATVTIFDD DHAGIFTFEE PVTHVSESIG IMEVKV LRT SGARGNVIVP YKTIEGTARG GGEDFEDTCG ELEFQNDEIV KIITIRIFDR EEYEKECSFS LVLEEPKWIR RGMKGGF TI TDEYDDKQPL TSKEEEERRI AEMGRPILGE HTKLEVIIEE SYEFKSTVDK LIKKTNLALV VGTNSWREQF IEAITVSA G EDDDDDECGE EKLPSCFDYV MHFLTVFWKV LFAFVPPTEY WNGWACFIVS ILMIGLLTAF IGDLASHFGC TIGLKDSVT AVVFVALGTS VPDTFASKVA ATQDQYADAS IGNVTGSNAV NVFLGIGVAW SIAAIYHAAN GEQFKVSPGT LAFSVTLFTI FAFINVGVL LYRRRPEIGG ELGGPRTAKL LTSCLFVLLW LLYIFFSSLE AYCHIKGF

UniProtKB: Sodium/calcium exchanger 1

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Macromolecule #2: 2-{4-[(2,5-difluorophenyl)methoxy]phenoxy}-5-ethoxyaniline

MacromoleculeName: 2-{4-[(2,5-difluorophenyl)methoxy]phenoxy}-5-ethoxyaniline
type: ligand / ID: 2 / Number of copies: 1 / Formula: EKY
Molecular weightTheoretical: 371.377 Da
Chemical component information

ChemComp-EKY:
2-{4-[(2,5-difluorophenyl)methoxy]phenoxy}-5-ethoxyaniline

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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: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / 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 / Nominal defocus max: 22.0 µm / Nominal defocus min: 12.0 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:

3v5s

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 177782
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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