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- PDB-9t5n: Structure of heteromeric mouse LRRC8A/D Volume-Regulated Anion Ch... -

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Basic information

Entry
Database: PDB / ID: 9t5n
TitleStructure of heteromeric mouse LRRC8A/D Volume-Regulated Anion Channel in complex with synthetic nanobody Sb1, Conformation 1
Components
  • Sb1
  • Volume-regulated anion channel subunit LRRC8A
  • Volume-regulated anion channel subunit LRRC8D
KeywordsMEMBRANE PROTEIN / Transmembrane protein / cell swelling
Function / homology
Function and homology information


Miscellaneous transport and binding events / pre-B cell differentiation / volume-sensitive anion channel activity / aspartate transmembrane transport / cyclic-GMP-AMP transmembrane transporter activity / cyclic-GMP-AMP transmembrane import across plasma membrane / monoatomic anion transmembrane transport / taurine transmembrane transport / cell volume homeostasis / monoatomic anion transport ...Miscellaneous transport and binding events / pre-B cell differentiation / volume-sensitive anion channel activity / aspartate transmembrane transport / cyclic-GMP-AMP transmembrane transporter activity / cyclic-GMP-AMP transmembrane import across plasma membrane / monoatomic anion transmembrane transport / taurine transmembrane transport / cell volume homeostasis / monoatomic anion transport / monoatomic ion channel complex / cellular response to osmotic stress / protein hexamerization / response to osmotic stress / positive regulation of myoblast differentiation / intracellular glucose homeostasis / chloride transmembrane transport / positive regulation of insulin secretion / spermatogenesis / lysosomal membrane / endoplasmic reticulum membrane / cell surface / membrane / identical protein binding / plasma membrane / cytoplasm
Similarity search - Function
LRRC8, pannexin-like TM region / Pannexin-like TM region of LRRC8 / : / : / Leucine-rich repeat region / Leucine-rich repeat, SDS22-like subfamily / Leucine rich repeat / Leucine-rich repeat, typical subtype / Leucine-rich repeats, typical (most populated) subfamily / Leucine-rich repeat profile. ...LRRC8, pannexin-like TM region / Pannexin-like TM region of LRRC8 / : / : / Leucine-rich repeat region / Leucine-rich repeat, SDS22-like subfamily / Leucine rich repeat / Leucine-rich repeat, typical subtype / Leucine-rich repeats, typical (most populated) subfamily / Leucine-rich repeat profile. / Leucine-rich repeat / Leucine-rich repeat domain superfamily
Similarity search - Domain/homology
Volume-regulated anion channel subunit LRRC8A / Volume-regulated anion channel subunit LRRC8D
Similarity search - Component
Biological speciesMus musculus (house mouse)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.02 Å
AuthorsLehmann, E.F. / Deneka, D. / Stierli, F. / Rutz, S. / Dutzler, R.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
Swiss National Science Foundation Switzerland
CitationJournal: Nat Commun / Year: 2026
Title: Structures of the volume-regulated anion channel LRRC8A/D in activating and inhibiting conditions.
Authors: Elena F Lehmann / Fabienne Stierli / Sonja Rutz / Dawid Deneka / Raimund Dutzler /
Abstract: Volume-regulated anion channels, which are activated in response to hypotonicity, are heteromers composed of LRRC8 family members. They consist of the obligatory subunit LRRC8A and at least another ...Volume-regulated anion channels, which are activated in response to hypotonicity, are heteromers composed of LRRC8 family members. They consist of the obligatory subunit LRRC8A and at least another paralog that determines their substrate preference. Here we investigate heteromeric assemblies composed of LRRC8A and D subunits, the latter of which confer permeability to amino acids, osmolytes and anti-cancer drugs. Using patch-clamp electrophysiology, we show that LRRC8A/D channels are reversibly activated by cell swelling and that their response is modulated by sybodies targeting the A subunits, which either potentiate or repress channel activity. Structures of the LRRC8A/D channel in complex with the inhibitory sybody Sb1 define the channel stoichiometry of four A and two D subunits, with Sb1 stabilizing the A subunits in a similar closed channel conformation as found in homomeric LRRC8A assemblies. In LRRC8A/D heteromers, the two D subunits weaken the arrangement of A subunits and thus enhance the activation properties of the channel. This channel conformation is strongly perturbed upon binding of the potentiating sybody Sb4, which disrupts the packing of the cytoplasmic domains linking their mobility to pore opening.
History
DepositionNov 5, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 2, 2026Provider: repository / Type: Initial release
Revision 1.0Sep 2, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.1Sep 30, 2026Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name / _em_admin.last_update
Revision 1.1Sep 30, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin
Data content type: EM metadata / EM metadata ...EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Volume-regulated anion channel subunit LRRC8A
B: Volume-regulated anion channel subunit LRRC8A
C: Volume-regulated anion channel subunit LRRC8A
D: Volume-regulated anion channel subunit LRRC8A
G: Sb1
H: Sb1
I: Sb1
J: Sb1
E: Volume-regulated anion channel subunit LRRC8D
F: Volume-regulated anion channel subunit LRRC8D


Theoretical massNumber of molelcules
Total (without water)643,83110
Polymers643,83110
Non-polymers00
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: Protein
Volume-regulated anion channel subunit LRRC8A / Leucine-rich repeat-containing protein 8A / Protein ebouriffe / ebo / Swelling protein 1


Mass: 95127.391 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Lrrc8a, Lrrc8, Swell1 / Production host: Homo sapiens (human) / References: UniProt: Q80WG5
#2: Antibody
Sb1


Mass: 13115.529 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli MC1061 (bacteria)
#3: Protein Volume-regulated anion channel subunit LRRC8D / Leucine-rich repeat-containing protein 5 / Leucine-rich repeat-containing protein 8D


Mass: 105429.789 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Lrrc8d, Lrrc5 / Production host: Homo sapiens (human) / References: UniProt: Q8BGR2
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: mouse LRRC8A/D in complex with synthetic nanobody Sb1, conformation 1
Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Mus musculus (house mouse)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE-PROPANE

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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: OTHER
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2400 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 63.03 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2PHENIX1.21.2_5419model refinement
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 3.02 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 387972 / Symmetry type: POINT
RefinementHighest resolution: 3.02 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00439864
ELECTRON MICROSCOPYf_angle_d0.45754024
ELECTRON MICROSCOPYf_dihedral_angle_d11.49814838
ELECTRON MICROSCOPYf_chiral_restr0.046174
ELECTRON MICROSCOPYf_plane_restr0.0036720

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