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- EMDB-48320: Cryo-EM structure of human NBCn2 bound to Compound 38J -

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Basic information

Entry
Database: EMDB / ID: EMD-48320
TitleCryo-EM structure of human NBCn2 bound to Compound 38J
Map dataCryo-EM map of human NBCn2 bound to Compound 38J
Sample
  • Complex: Dimeric NBCn2
    • Protein or peptide: Sodium-driven chloride bicarbonate exchanger
  • Ligand: CHOLESTEROL
  • Ligand: ethyl [(8R)-2-{[(3-methylphenyl)methyl]amino}-7-oxo-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]acetate
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsTransmembrane / Transport Protein / MEMBRANE PROTEIN
Function / homology
Function and homology information


sodium,bicarbonate:chloride antiporter activity / CA3 pyramidal cell dendrite / sodium:bicarbonate symporter activity / basal dendrite / Bicarbonate transporters / solute:inorganic anion antiporter activity / regulation of short-term neuronal synaptic plasticity / bicarbonate transport / apical dendrite / chloride transport ...sodium,bicarbonate:chloride antiporter activity / CA3 pyramidal cell dendrite / sodium:bicarbonate symporter activity / basal dendrite / Bicarbonate transporters / solute:inorganic anion antiporter activity / regulation of short-term neuronal synaptic plasticity / bicarbonate transport / apical dendrite / chloride transport / visual perception / somatodendritic compartment / axon terminus / regulation of intracellular pH / GABA-ergic synapse / transmembrane transport / basolateral plasma membrane / perikaryon / postsynapse / apical plasma membrane / neuronal cell body / dendrite / synapse / membrane / plasma membrane
Similarity search - Function
Sodium bicarbonate cotransporter / Band 3 cytoplasmic domain / Band 3 cytoplasmic domain / Phosphotransferase/anion transporter / Bicarbonate transporter, eukaryotic / Bicarbonate transporter-like, transmembrane domain / HCO3- transporter integral membrane domain
Similarity search - Domain/homology
Sodium-driven chloride bicarbonate exchanger
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.24 Å
AuthorsYang S / Capper MJ / Zilberg G / Warren AL / Wacker D
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35 GM133504 United States
CitationJournal: Nat Commun / Year: 2026
Title: Structural insights enable drug discovery for the neuronal NBCn2 carbonate transporter.
Authors: Shifan Yang / Yihan Zhao / Sezen Vatansever / Gregory Zilberg / Michael J Capper / Jinglong Zhang / Joshua Stamos / Keino Hutchinson / Audrey L Warren / Alexander C Stone / Anwar Abbassi / ...Authors: Shifan Yang / Yihan Zhao / Sezen Vatansever / Gregory Zilberg / Michael J Capper / Jinglong Zhang / Joshua Stamos / Keino Hutchinson / Audrey L Warren / Alexander C Stone / Anwar Abbassi / Eric Purisic / Lap Ho / Aiqun Li / Jinye Dai / Avner Schlessinger / Bin Zhang / Daniel Wacker /
Abstract: NBCn2 (SLC4A10), a member of the SLC4 solute carrier (SLC) family, is a sodium-dependent (bi)carbonate transporter that regulates acid extrusion in various brain regions. Mutations in NBCn2 cause ...NBCn2 (SLC4A10), a member of the SLC4 solute carrier (SLC) family, is a sodium-dependent (bi)carbonate transporter that regulates acid extrusion in various brain regions. Mutations in NBCn2 cause severe neurodevelopmental disorders in humans, and knock out studies suggest that its role in regulating neuronal excitability could hold therapeutic potential for seizure disorders such as epilepsy. Despite its physiological importance, NBCn2's molecular mechanisms remain largely unknown, and there is limited availability of tool compounds to further probe its role in health and disease. Combining cryoEM with computational docking and simulation studies, we herein elucidate NBCn2's molecular architecture and substrate binding mechanisms on the atomic scale. Via structure-based drug discovery we further identify a compound series that inhibits NBCn2-mediated transport, and characterize its inhibitory mechanisms via cryoEM. Lastly, we showcase the potential of this compound series to template useful probes by demonstrating pharmacological activity both in primary culture as well as brain slices.
History
DepositionDec 16, 2024-
Header (metadata) releaseAug 5, 2026-
Map releaseAug 5, 2026-
UpdateSep 9, 2026-
Current statusSep 9, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_48320.png

Downloads & links

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Map

FileDownload / File: emd_48320.map.gz / Format: CCP4 / Size: 144.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM map of human NBCn2 bound to Compound 38J
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 336 pix.
= 359.184 Å		1.07 Å/pix.
x 336 pix.
= 359.184 Å		1.07 Å/pix.
x 336 pix.
= 359.184 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.069 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.15
Minimum - Maximum-1.0998116 - 1.6710408
Average (Standard dev.)0.000000000128481 (±0.02400274)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions336336336
Spacing336336336
CellA=B=C: 359.184 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half A map of human NBCn2 bound to Compound 38J

Fileemd_48320_half_map_1.map
AnnotationHalf A map of human NBCn2 bound to Compound 38J
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half B map of human NBCn2 bound to Compound 38J

Fileemd_48320_half_map_2.map
AnnotationHalf B map of human NBCn2 bound to Compound 38J
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Dimeric NBCn2

EntireName: Dimeric NBCn2
Components
  • Complex: Dimeric NBCn2
    • Protein or peptide: Sodium-driven chloride bicarbonate exchanger
  • Ligand: CHOLESTEROL
  • Ligand: ethyl [(8R)-2-{[(3-methylphenyl)methyl]amino}-7-oxo-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]acetate
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Dimeric NBCn2

SupramoleculeName: Dimeric NBCn2 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 220 KDa

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Macromolecule #1: Sodium-driven chloride bicarbonate exchanger

MacromoleculeName: Sodium-driven chloride bicarbonate exchanger / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 110.991359 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MSFDTPSQRV QFILGTEDDD EEHIPHDLFT ELDEICWREG EDAEWRETAR WLKFEEDVED GGERWSKPYV ATLSLHSLFE LRSCILNGT VLLDMHANTL EEIADMVLDQ QVSSGQLNED VRHRVHEALM KQHHHQNQKK LTGMKQRHEK GPPHQQEREV D LHFMKKIP ...String:
MSFDTPSQRV QFILGTEDDD EEHIPHDLFT ELDEICWREG EDAEWRETAR WLKFEEDVED GGERWSKPYV ATLSLHSLFE LRSCILNGT VLLDMHANTL EEIADMVLDQ QVSSGQLNED VRHRVHEALM KQHHHQNQKK LTGMKQRHEK GPPHQQEREV D LHFMKKIP PGAEASNILV GELEFLDRTV VAFVRLSPAV LLQGLAEVPI PTRFLFILLG PLGKGQQYHE IGRSIATLMT DE VFHDVAY KAKDRNDLVS GIDEFLDQVT VLPPGEWDPS IRIEPPKNVP SQEKRKIPAV PNGTAAHGEA EPHGGHSGPE LQR TGRIFG GLILDIKRKA PYFWSDFRDA FSLQCLASFL FLYCACMSPV ITFGGLLGEA TEGRISAIES LFGASMTGIA YSLF GGQPL TILGSTGPVL VFEKILFKFC KEYGLSYLSL RASIGLWTAT LCIILVATDA SSLVCYITRF TEEAFASLIC IIFIY EALE KLFELSEAYP INMHNDLELL TQYSCNCVEP HNPSNGTLKE WRESNISASD IIWENLTVSE CKSLHGEYVG RACGHD HPY VPDVLFWSVI LFFSTVTLSA TLKQFKTSRY FPTKVRSIVS DFAVFLTILC MVLIDYAIGI PSPKLQVPSV FKPTRDD RG WFVTPLGPNP WWTVIAAIIP ALLCTILIFM DQQITAVIIN RKEHKLKKGC GYHLDLLMVA VMLGVCSIMG LPWFVAAT V LSITHVNSLK LESECSAPGE QPKFLGIREQ RVTGLMIFIL MGSSVFMTSI LKFIPMPVLY GVFLYMGASS LKGIQFFDR IKLFWMPAKH QPDFIYLRHV PLRKVHLFTI IQMSCLGLLW IIKVSRAAIV FPMMVLALVF VRKLMDLLFT KRELSWLDDL MPESKKKKL EDAEKEEEQS MLAMEDEGTV QLPLEGHYRD DPSVINISDE MSKTALWRNL LITADNSKDK ESSFPSKSSP S GRPLEVLF QGPHHHHHHH HHH

UniProtKB: Sodium-driven chloride bicarbonate exchanger

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Macromolecule #2: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 2 / Number of copies: 8 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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Macromolecule #3: ethyl [(8R)-2-{[(3-methylphenyl)methyl]amino}-7-oxo-4,7-dihydro[1...

MacromoleculeName: ethyl [(8R)-2-{[(3-methylphenyl)methyl]amino}-7-oxo-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]acetate
type: ligand / ID: 3 / Number of copies: 2 / Formula: A1BLW
Molecular weightTheoretical: 341.364 Da

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Macromolecule #4: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 4 / Number of copies: 2 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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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
Component:
ConcentrationName
20.0 mMHEPES
150.0 mMSodium Chloride
0.0011 % (w/v)LMNG
0.00011 % (w/v)CHS
0.00025 % (w/v)GDN
0.1 mMCompound 38J
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 285 K / Instrument: LEICA EM GP / Details: Blot force 3 for 3 seconds.

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 52.48 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: 1.8 µm / Nominal defocus min: 0.5 µm
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

Particle selectionNumber selected: 794592
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.24 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 216501
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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