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- PDB-9g6c: CLC7/OSTM1 complex with bound PIP2 lipid -

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Basic information

Entry
Database: PDB / ID: 9g6c
TitleCLC7/OSTM1 complex with bound PIP2 lipid
Components
  • H(+)/Cl(-) exchange transporter 7
  • Osteopetrosis-associated transmembrane protein 1
KeywordsMEMBRANE PROTEIN / Lysosomal transporter / pH Regulation / Membrane Complex / Transporter
Function / homology
Function and homology information


transepithelial chloride transport / chloride:proton antiporter activity / response to pH / chloride transmembrane transporter activity / chloride channel activity / chloride channel complex / osteoclast differentiation / Stimuli-sensing channels / lysosomal membrane / intracellular membrane-bounded organelle ...transepithelial chloride transport / chloride:proton antiporter activity / response to pH / chloride transmembrane transporter activity / chloride channel activity / chloride channel complex / osteoclast differentiation / Stimuli-sensing channels / lysosomal membrane / intracellular membrane-bounded organelle / ATP binding / membrane / cytosol
Similarity search - Function
Osteopetrosis-associated transmembrane protein 1 precursor / Osteopetrosis-associated transmembrane protein 1 precursor / Chloride channel ClC-7 / : / Chloride channel, voltage gated / Chloride channel, core / Voltage gated chloride channel / Domain in cystathionine beta-synthase and other proteins. / CBS domain superfamily / CBS domain ...Osteopetrosis-associated transmembrane protein 1 precursor / Osteopetrosis-associated transmembrane protein 1 precursor / Chloride channel ClC-7 / : / 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
: / ADENOSINE-5'-TRIPHOSPHATE / CHOLESTEROL HEMISUCCINATE / H(+)/Cl(-) exchange transporter 7 / Osteopetrosis-associated transmembrane protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 1.8 Å
AuthorsLin, Y. / Deme, J.C. / Lea, S.M. / Newstead, S.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Wellcome Trust United Kingdom
CitationJournal: bioRxiv / Year: 2025
Title: Mechanism of phosphoinositide regulation of lysosomal pH via inhibition of CLC-7.
Authors: Jacob K Hilton / Yifei Lin / Eric Sefah / Justin C Deme / Joanne L Parker / Matthew J Langton / Michael Grabe / Susan Lea / Simon Newstead / Joseph A Mindell /
Abstract: Lysosomes process cellular waste and coordinate responses to metabolic challenge. Central to lysosomal homeostasis are phosphoinositide lipids, key signaling molecules which establish organelle ...Lysosomes process cellular waste and coordinate responses to metabolic challenge. Central to lysosomal homeostasis are phosphoinositide lipids, key signaling molecules which establish organelle identity, regulate membrane dynamics and are tightly linked to the pathophysiology and therapy of lysosomal storage disorders, neurodegeneration, and cancer. Phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) interacts with multiple lysosomal membrane proteins and plays a critical role in regulating lysosomal pH by directly inhibiting the chloride/proton antiporter ClC-7, though the molecular mechanism of this inhibition remains unclear. Here, using a combination of functional, structural, and computational analysis, we demonstrate that PI(3,5)P2 binding dramatically remodels the structure of ClC-7 by inducing close association between cytosolic and transmembrane domains. Disease-causing mutations show increased transport activity through loss of PI(3,5)P2 binding and subsequent inhibition. Conversely, ClC-7 activation is correlated with dissociation and increased disorder of the cytoplasmic domain along with novel transmembrane domain conformations, revealing a mechanistic link between specific lysosomal lipids, transporter regulation, and the enigmatic basis of the ClC-7 slow gate.
History
DepositionJul 18, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 30, 2025Provider: repository / Type: Initial release
Revision 1.0Jul 30, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jul 30, 2025Data content type: Additional map / Part number: 1 / Data content type: Additional map / Provider: repository / Type: Initial release
Revision 1.0Jul 30, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jul 30, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.0Jul 30, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jul 30, 2025Data content type: Mask / Part number: 1 / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0Jul 30, 2025Data content type: Mask / Part number: 2 / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0Jul 30, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Dec 10, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: H(+)/Cl(-) exchange transporter 7
B: Osteopetrosis-associated transmembrane protein 1
C: H(+)/Cl(-) exchange transporter 7
D: Osteopetrosis-associated transmembrane protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)258,79224
Polymers252,1294
Non-polymers6,66320
Water6,774376
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

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Protein , 2 types, 4 molecules ACBD

#1: Protein H(+)/Cl(-) exchange transporter 7 / Chloride channel 7 alpha subunit / Chloride channel protein 7 / ClC-7


Mass: 88773.875 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CLCN7 / Production host: Homo sapiens (human) / References: UniProt: P51798
#2: Protein Osteopetrosis-associated transmembrane protein 1 / Chloride channel 7 beta subunit


Mass: 37290.570 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: OSTM1, GL, HSPC019, UNQ6098/PRO21201 / Production host: Homo sapiens (human) / References: UniProt: Q86WC4

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Non-polymers , 6 types, 396 molecules

#3: Chemical ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE


Mass: 507.181 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C10H16N5O13P3 / Feature type: SUBJECT OF INVESTIGATION / Comment: ATP, energy-carrying molecule*YM
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Cl / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-A1IIT / [(2R)-2-octanoyloxy-3-[oxidanyl-[(1S,2R,3S,4R,5R,6R)-2,4,5-tris(oxidanyl)-3,6-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate / PI(2,5)P2


Mass: 746.566 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H49O19P3 / Feature type: SUBJECT OF INVESTIGATION
#7: Chemical
ChemComp-Y01 / CHOLESTEROL HEMISUCCINATE


Mass: 486.726 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C31H50O4
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 376 / Source method: isolated from a natural source / Formula: H2O

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Details

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: Hetero-tetrameric Complex of WTCLC7/OSTM1 with PIP2 Bound
Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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: 2500 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 55.7 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 1.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 833576 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00215080
ELECTRON MICROSCOPYf_angle_d0.45920516
ELECTRON MICROSCOPYf_dihedral_angle_d8.0942316
ELECTRON MICROSCOPYf_chiral_restr0.0362393
ELECTRON MICROSCOPYf_plane_restr0.0042499

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