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- PDB-9qub: Cryo-EM structure of the human NHA2-Fab complex -

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Basic information

Entry
Database: PDB / ID: 9qub
TitleCryo-EM structure of the human NHA2-Fab complex
Components
  • Fab-heavy chain
  • Fab-light chain
  • Sodium/hydrogen exchanger 9B2
KeywordsTRANSPORT PROTEIN / Na+/H+ exchanger
Function / homology
Function and homology information


lithium:proton antiporter activity / lithium ion transport / positive regulation of osteoclast development / sperm principal piece / sodium ion homeostasis / sodium:proton antiporter activity / regulation of insulin secretion involved in cellular response to glucose stimulus / clathrin-dependent endocytosis / flagellated sperm motility / : ...lithium:proton antiporter activity / lithium ion transport / positive regulation of osteoclast development / sperm principal piece / sodium ion homeostasis / sodium:proton antiporter activity / regulation of insulin secretion involved in cellular response to glucose stimulus / clathrin-dependent endocytosis / flagellated sperm motility / : / sodium ion transport / recycling endosome / mitochondrial membrane / Stimuli-sensing channels / recycling endosome membrane / synaptic vesicle membrane / monoatomic ion transmembrane transport / basolateral plasma membrane / mitochondrial inner membrane / apical plasma membrane / mitochondrion / identical protein binding / plasma membrane
Similarity search - Function
: / Sodium/solute symporter superfamily / Cation/H+ exchanger / Sodium/hydrogen exchanger, transmembrane
Similarity search - Domain/homology
Chem-LPP / Sodium/hydrogen exchanger 9B2
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.7 Å
AuthorsJung, S. / Drew, D.
Funding supportEuropean Union, 1items
OrganizationGrant numberCountry
European Research Council (ERC)820187European Union
CitationJournal: Int J Mol Sci / Year: 2025
Title: Structure and Inhibition of the Human Na/H Exchanger SLC9B2.
Authors: Sukkyeong Jung / Surabhi Kokane / Hang Li / So Iwata / Norimichi Nomura / David Drew /
Abstract: The sodium/proton exchanger NHA2, also known as SLC9B2, is important for insulin secretion, renal blood pressure regulation, and electrolyte retention. Recent structures of bison NHA2 has revealed ...The sodium/proton exchanger NHA2, also known as SLC9B2, is important for insulin secretion, renal blood pressure regulation, and electrolyte retention. Recent structures of bison NHA2 has revealed its unique 14-transmembrane helix architecture, which is different from SLC9A/NHE members made up from 13-TM helices. Sodium/proton exchangers are functional homodimers, and the additional N-terminal helix in NHA2 was found to alter homodimer assembly. Here, we present the cryo-electron microscopy structures of apo human NHA2 in complex with a Fab fragment and also with the inhibitor phloretin bound at 2.8 and 2.9 Å resolution, respectively. We show how phosphatidic acid (PA) lipids bind to the homodimer interface of NHA2 on the extracellular side, which we propose has a regulatory role linked to cell volume regulation. The ion binding site of human NHA2 has a salt bridge interaction between the ion binding aspartate D278 and R432, an interaction previously broken in the bison NHA2 structure, and these differences suggest a possible ion coupling mechanism. Lastly, the human NHA2 structure in complex with phloretin offers a template for structure-guided drug design, potentially leading to the development of more selective and potent NHA2 inhibitors.
History
DepositionApr 10, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 14, 2025Provider: repository / Type: Initial release
Revision 1.1May 28, 2025Group: Data collection / Database references / Category: citation / em_admin
Item: _citation.journal_volume / _citation.pdbx_database_id_PubMed ..._citation.journal_volume / _citation.pdbx_database_id_PubMed / _citation.title / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
C: Fab-light chain
E: Fab-light chain
D: Fab-heavy chain
F: Fab-heavy chain
B: Sodium/hydrogen exchanger 9B2
A: Sodium/hydrogen exchanger 9B2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)219,4668
Polymers218,1696
Non-polymers1,2982
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Antibody Fab-light chain


Mass: 23715.109 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse)
#2: Antibody Fab-heavy chain


Mass: 27757.529 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse)
#3: Protein Sodium/hydrogen exchanger 9B2 / Na(+)/H(+) exchanger NHA2 / Na(+)/H(+) exchanger-like domain-containing protein 2 / NHE domain- ...Na(+)/H(+) exchanger NHA2 / Na(+)/H(+) exchanger-like domain-containing protein 2 / NHE domain-containing protein 2 / Sodium/hydrogen exchanger-like domain-containing protein 2 / Solute carrier family 9 subfamily B member 2


Mass: 57611.672 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC9B2, NHA2, NHEDC2 / Production host: Saccharomyces cerevisiae (brewer's yeast) / References: UniProt: Q86UD5
#4: Chemical ChemComp-LPP / 2-(HEXADECANOYLOXY)-1-[(PHOSPHONOOXY)METHYL]ETHYL HEXADECANOATE / 1,2-DIPALMITOYL-SN-GLYCERO-3-PHOSPHATE / L-B,G-DIPALMITOYL-A-PHOSPHATIDIC ACID DISODIUM SALT / 3-SN-PHOSPHATIDIC ACID / 1,2-DIPALMITOYLDISODIUM SALT


Mass: 648.891 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C35H69O8P / Feature type: SUBJECT OF INVESTIGATION / Comment: phospholipid*YM
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: Complex of human NHA2 with Fab / Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Saccharomyces cerevisiae (brewer's yeast)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE / Humidity: 100 %

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
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: 600 nm
Image recordingElectron dose: 62.4 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 332205 / Symmetry type: POINT
RefinementHighest resolution: 2.7 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00413167
ELECTRON MICROSCOPYf_angle_d0.54517895
ELECTRON MICROSCOPYf_dihedral_angle_d5.5781836
ELECTRON MICROSCOPYf_chiral_restr0.0392108
ELECTRON MICROSCOPYf_plane_restr0.0032203

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