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- PDB-9iv8: Cryo-EM structure of human NCX1 in PIP2 diC8 bound state -

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Basic information

Entry
Database: PDB / ID: 9iv8
TitleCryo-EM structure of human NCX1 in PIP2 diC8 bound state
ComponentsSodium/calcium exchanger 1
KeywordsTRANSPORT PROTEIN / sodium calcium exchanger / Na/Ca exchanger
Function / homology
Function and homology information


relaxation of smooth muscle / calcium:sodium antiporter activity / vascular associated smooth muscle contraction / regulation of cell communication by electrical coupling / negative regulation of protein serine/threonine kinase activity / calcium ion export / membrane depolarization during cardiac muscle cell action potential / sodium ion export across plasma membrane / regulation of the force of heart contraction / cell communication by electrical coupling involved in cardiac conduction ...relaxation of smooth muscle / calcium:sodium antiporter activity / vascular associated smooth muscle contraction / regulation of cell communication by electrical coupling / negative regulation of protein serine/threonine kinase activity / calcium ion export / membrane depolarization during cardiac muscle cell action potential / sodium ion export across plasma membrane / regulation of the force of heart contraction / cell communication by electrical coupling involved in cardiac conduction / intracellular sodium ion homeostasis / sodium ion import across plasma membrane / calcium ion import / calcium ion transport into cytosol / Sodium/Calcium exchangers / cardiac muscle cell development / regulation of cardiac muscle contraction by calcium ion signaling / Reduction of cytosolic Ca++ levels / ankyrin binding / relaxation of cardiac muscle / calcium ion transmembrane import into cytosol / negative regulation of cytosolic calcium ion concentration / cellular response to caffeine / positive regulation of the force of heart contraction / calcium ion import across plasma membrane / intercalated disc / regulation of cardiac conduction / positive regulation of bone mineralization / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / calcium ion homeostasis / Ion homeostasis / cytoskeletal protein binding / monoatomic ion transport / cardiac muscle contraction / muscle contraction / axon terminus / response to muscle stretch / T-tubule / sodium ion transmembrane transport / regulation of heart rate / cell periphery / cellular response to reactive oxygen species / sarcolemma / calcium ion transmembrane transport / Z disc / intracellular calcium ion homeostasis / regulation of gene expression / transmembrane transporter binding / postsynapse / calmodulin binding / postsynaptic density / axon / neuronal cell body / synapse / dendrite / calcium ion binding / 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 / Sodium/calcium exchanger membrane region / NCX, central ion-binding domain superfamily ...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 / Sodium/calcium exchanger membrane region / NCX, central ion-binding domain superfamily / Sodium/calcium exchanger protein / CalX-like domain superfamily / DnaJ domain
Similarity search - Domain/homology
Chem-PIO / Sodium/calcium exchanger 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsXue, J. / Jiang, Y.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM140892 United States
Welch FoundationI-1578 United States
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: Elife / Year: 2025
Title: Structural mechanisms of PIP activation and SEA0400 inhibition in human cardiac sodium-calcium exchanger NCX1.
Authors: Jing Xue / Weizhong Zeng / Scott John / Nicole Attiq / Michela Ottolia / Youxing Jiang /
Abstract: Na/Ca exchangers (NCXs) transport Ca across the plasma membrane in exchange for Na and play a vital role in maintaining cellular Ca homeostasis. Our previous structural study of human cardiac NCX1 ...Na/Ca exchangers (NCXs) transport Ca across the plasma membrane in exchange for Na and play a vital role in maintaining cellular Ca homeostasis. Our previous structural study of human cardiac NCX1 (HsNCX1) reveals the overall architecture of the eukaryotic exchanger and the formation of the inactivation assembly by the intracellular regulatory domain that underlies the cytosolic Na-dependent inactivation and Ca activation of NCX1. Here, we present the cryo-EM structures of HsNCX1 in complex with a physiological activator phosphatidylinositol 4,5-bisphosphate (PIP), or pharmacological inhibitor SEA0400, that enhances the inactivation of the exchanger. We demonstrate that PIP binding stimulates NCX1 activity by inducing a conformational change at the interface between the transmembrane (TM) and cytosolic domains that destabilizes the inactivation assembly. In contrast, SEA0400 binding in the TM domain of NCX1 stabilizes the exchanger in an inward-facing conformation that facilitates the formation of the inactivation assembly, thereby promoting the Na-dependent inactivation of NCX1. Thus, this study reveals the structural basis of PIP activation and SEA0400 inhibition of NCX1 and provides some mechanistic understandings of cellular regulation and pharmacology of NCX family proteins.
History
DepositionJul 23, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 19, 2025Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Sodium/calcium exchanger 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)110,1287
Polymers109,1811
Non-polymers9476
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Sodium/calcium exchanger 1 / Na(+)/Ca(2+)-exchange protein 1 / Solute carrier family 8 member 1


Mass: 109181.070 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC8A1, CNC, NCX1 / Production host: Homo sapiens (human) / References: UniProt: P32418
#2: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Ca / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-PIO / [(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate / dioctanoyl l-alpha-phosphatidyl-d-myo-inositol 4,5-diphosphate


Mass: 746.566 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H49O19P3 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: human cardiac sodium calcium exchanger NCX1 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

MicroscopyModel: FEI TECNAI SPHERA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

CTF correctionType: NONE
3D reconstructionResolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 117748 / Symmetry type: POINT
RefinementHighest resolution: 3.5 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0046077
ELECTRON MICROSCOPYf_angle_d0.6838246
ELECTRON MICROSCOPYf_dihedral_angle_d5.116829
ELECTRON MICROSCOPYf_chiral_restr0.049953
ELECTRON MICROSCOPYf_plane_restr0.0051026

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