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- EMDB-36238: Cryo-EM structure of mClC-3 with AMP -

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Basic information

Entry
Database: EMDB / ID: EMD-36238
TitleCryo-EM structure of mClC-3 with AMP
Map data
Sample
  • Complex: mClC-3 with AMP
    • Protein or peptide: H(+)/Cl(-) exchange transporter 3
  • Ligand: ADENOSINE MONOPHOSPHATE
  • Ligand: water
KeywordsMEMBRANE PROTEIN
Function / homology
Function and homology information


volume-sensitive chloride channel activity / chloride:proton antiporter activity / synaptic vesicle lumen acidification / inhibitory synapse / negative regulation of cell volume / voltage-gated chloride channel activity / specific granule / photoreceptor cell maintenance / vesicle membrane / antiporter activity ...volume-sensitive chloride channel activity / chloride:proton antiporter activity / synaptic vesicle lumen acidification / inhibitory synapse / negative regulation of cell volume / voltage-gated chloride channel activity / specific granule / photoreceptor cell maintenance / vesicle membrane / antiporter activity / synaptic transmission, GABAergic / phagocytosis, engulfment / positive regulation of reactive oxygen species biosynthetic process / phagocytic vesicle / axon terminus / adult locomotory behavior / GABA-ergic synapse / synaptic transmission, glutamatergic / PDZ domain binding / recycling endosome / neuron cellular homeostasis / synaptic vesicle membrane / recycling endosome membrane / late endosome membrane / late endosome / synaptic vesicle / early endosome membrane / early endosome / endosome / endosome membrane / external side of plasma membrane / lysosomal membrane / glutamatergic synapse / Golgi apparatus / ATP binding / plasma membrane
Similarity search - Function
Chloride channel ClC-3 / Chloride channel, voltage gated / Chloride channel, core / Voltage gated chloride channel / Domain in cystathionine beta-synthase and other proteins. / CBS domain superfamily / CBS domain / CBS domain / CBS domain profile.
Similarity search - Domain/homology
H(+)/Cl(-) exchange transporter 3
Similarity search - Component
Biological speciesMus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.14 Å
AuthorsWan YZQ / Yang F
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32122040 China
CitationJournal: Nat Commun / Year: 2024
Title: Structural basis of adenine nucleotides regulation and neurodegenerative pathology in ClC-3 exchanger.
Authors: Yangzhuoqun Wan / Shuangshuang Guo / Wenxuan Zhen / Lizhen Xu / Xiaoying Chen / Fangyue Liu / Yi Shen / Shuangshuang Liu / Lidan Hu / Xinyan Wang / Fengcan Ye / Qinrui Wang / Han Wen / Fan Yang /
Abstract: The ClC-3 chloride/proton exchanger is both physiologically and pathologically critical, as it is potentiated by ATP to detect metabolic energy level and point mutations in ClC-3 lead to severe ...The ClC-3 chloride/proton exchanger is both physiologically and pathologically critical, as it is potentiated by ATP to detect metabolic energy level and point mutations in ClC-3 lead to severe neurodegenerative diseases in human. However, why this exchanger is differentially modulated by ATP, ADP or AMP and how mutations caused gain-of-function remains largely unknow. Here we determine the high-resolution structures of dimeric wildtype ClC-3 in the apo state and in complex with ATP, ADP and AMP, and the disease-causing I607T mutant in the apo and ATP-bounded state by cryo-electron microscopy. In combination with patch-clamp recordings and molecular dynamic simulations, we reveal how the adenine nucleotides binds to ClC-3 and changes in ion occupancy between apo and ATP-bounded state. We further observe I607T mutation induced conformational changes and augments in current. Therefore, our study not only lays the structural basis of adenine nucleotides regulation in ClC-3, but also clearly indicates the target region for drug discovery against ClC-3 mediated neurodegenerative diseases.
History
DepositionMay 21, 2023-
Header (metadata) releaseSep 11, 2024-
Map releaseSep 11, 2024-
UpdateOct 23, 2024-
Current statusOct 23, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_36238.png

Downloads & links

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Map

FileDownload / File: emd_36238.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.)
0.93 Å/pix.
x 256 pix.
= 238.08 Å		0.93 Å/pix.
x 256 pix.
= 238.08 Å		0.93 Å/pix.
x 256 pix.
= 238.08 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.93 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.197
Minimum - Maximum-1.0695896 - 1.5707543
Average (Standard dev.)0.00014243588 (±0.038230468)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 238.08 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : mClC-3 with AMP

EntireName: mClC-3 with AMP
Components
  • Complex: mClC-3 with AMP
    • Protein or peptide: H(+)/Cl(-) exchange transporter 3
  • Ligand: ADENOSINE MONOPHOSPHATE
  • Ligand: water

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Supramolecule #1: mClC-3 with AMP

SupramoleculeName: mClC-3 with AMP / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Mus musculus (house mouse)

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Macromolecule #1: H(+)/Cl(-) exchange transporter 3

MacromoleculeName: H(+)/Cl(-) exchange transporter 3 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 90.95782 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MESEQLFHRG YYRNSYNSIT SASSDEELLD GAGAIMDFQT SEDDNLLDGD TAAGTHYTMT NGGSINSSTH LLDLLDEPIP GVGTYDDFH TIDWVREKCK DRERHRRINS KKKESAWEMT KSLYDAWSGW LVVTLTGLAS GALAGLIDIA ADWMTDLKEG I CLSALWYN ...String:
MESEQLFHRG YYRNSYNSIT SASSDEELLD GAGAIMDFQT SEDDNLLDGD TAAGTHYTMT NGGSINSSTH LLDLLDEPIP GVGTYDDFH TIDWVREKCK DRERHRRINS KKKESAWEMT KSLYDAWSGW LVVTLTGLAS GALAGLIDIA ADWMTDLKEG I CLSALWYN HEQCCWGSNE TTFEERDKCP QWKTWAELII GQAEGPGSYI MNYIMYIFWA LSFAFLAVSL VKVFAPYACG SG IPEIKTI LSGFIIRGYL GKWTLMIKTI TLVLAVASGL SLGKEGPLVH VACCCGNIFS YLFPKYSTNE AKKREVLSAA SAA GVSVAF GAPIGGVLFS LEEVSYYFPL KTLWRSFFAA LVAAFVLRSI NPFGNSRLVL FYVEYHTPWY LFELFPFILL GVFG GLWGA FFIRANIAWC RRRKSTKFGK YPVLEVIIVA AITAVIAFPN PYTRLNTSEL IKELFTDCGP LESSSLCDYR NDMNA SKIV DDIPDRPAGV GVYSAIWQLC LALIFKIIMT VFTFGIKVPS GLFIPSMAIG AIAGRIVGIA VEQLAYYHHD WFIFKE WCE VGADCITPGL YAMVGAAACL GGVTRMTVSL VVIVFELTGG LEYIVPLMAA VMTSKWVGDA FGREGIYEAH IRLNGYP FL DAKEEFTHTT LAADVMRPRR SDPPLAVLTQ DNMTVDDIEN MINETSYNGF PVIMSKESQR LVGFALRRDL TIAIESAR K KQEGIVGSSR VCFAQHTPSL PAESPRPLKL RSILDMSPFT VTDHTPMEIV VDIFRKLGLR QCLVTHNGRL LGIITKKDI LRHMAQTANQ DPASIMFN

UniProtKB: H(+)/Cl(-) exchange transporter 3

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Macromolecule #2: ADENOSINE MONOPHOSPHATE

MacromoleculeName: ADENOSINE MONOPHOSPHATE / type: ligand / ID: 2 / Number of copies: 2 / Formula: AMP
Molecular weightTheoretical: 347.221 Da
Chemical component information

ChemComp-AMP:
ADENOSINE MONOPHOSPHATE / AMP*YM

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Macromolecule #3: water

MacromoleculeName: water / type: ligand / ID: 3 / Number of copies: 2 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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

Concentration5 mg/mL
BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 52.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.6 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.14 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 84022
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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