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- PDB-9t5q: LRR domain Structure of LRRC8A in complex with synthetic nanobody Sb4 -

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Basic information

Entry
Database: PDB / ID: 9t5q
TitleLRR domain Structure of LRRC8A in complex with synthetic nanobody Sb4
Components
  • Sb4
  • Volume-regulated anion channel subunit LRRC8A
KeywordsCYTOSOLIC PROTEIN / Cytosolic domain of LRRC8A in complex with Sb4
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 / 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 / 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
Similarity search - Component
Biological speciesMus musculus (house mouse)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 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 1.1Sep 30, 2026Group: Database references / Category: citation / citation_author
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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Volume-regulated anion channel subunit LRRC8A
I: Sb4
B: Volume-regulated anion channel subunit LRRC8A
C: Sb4


Theoretical massNumber of molelcules
Total (without water)123,9254
Polymers123,9254
Non-polymers00
Water15,097838
1
A: Volume-regulated anion channel subunit LRRC8A
I: Sb4


Theoretical massNumber of molelcules
Total (without water)61,9622
Polymers61,9622
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Volume-regulated anion channel subunit LRRC8A
C: Sb4


Theoretical massNumber of molelcules
Total (without water)61,9622
Polymers61,9622
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)55.948, 73.486, 81.924
Angle α, β, γ (deg.)111.037, 94.349, 110.313
Int Tables number1
Space group name H-MP1
Space group name HallP1

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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: 48071.082 Da / Num. of mol.: 2
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 Sb4


Mass: 13891.195 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli MC1061 (bacteria)
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 838 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.32 Å3/Da / Density % sol: 46.89 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop
Details: 20% (w/v) PEG 4000, 10 % (v/v) 2-PropOH and 0.1 M HEPES, pH 7.5

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Data collection

DiffractionMean temperature: 80 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS4 X 2M / Detector: PIXEL / Date: Mar 21, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.6→40.08 Å / Num. obs: 142196 / % possible obs: 96.96 % / Redundancy: 26.1 % / Rmerge(I) obs: 9.99 / Net I/σ(I): 11.74
Reflection shellResolution: 1.6→1.62 Å / Rmerge(I) obs: 9.99 / Num. unique obs: 142196

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Processing

Software
NameVersionClassification
PHENIX1.21.2_5419+SVNrefinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.6→40.08 Å / SU ML: 0.1822 / Cross valid method: FREE R-VALUE / σ(F): 1.97 / Phase error: 23.1128
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2289 7109 5 %
Rwork0.1984 135087 -
obs0.1999 142196 96.96 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 22.96 Å2
Refinement stepCycle: LAST / Resolution: 1.6→40.08 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8423 0 0 838 9261
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00578580
X-RAY DIFFRACTIONf_angle_d0.830611639
X-RAY DIFFRACTIONf_chiral_restr0.05281358
X-RAY DIFFRACTIONf_plane_restr0.00691471
X-RAY DIFFRACTIONf_dihedral_angle_d15.16433229
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.6-1.620.33622280.26974334X-RAY DIFFRACTION95.4
1.62-1.640.28562350.26324453X-RAY DIFFRACTION95.01
1.64-1.660.30182320.264411X-RAY DIFFRACTION95.24
1.66-1.680.29272330.25084423X-RAY DIFFRACTION95.45
1.68-1.70.2522320.23184425X-RAY DIFFRACTION95.25
1.7-1.720.25692340.23714444X-RAY DIFFRACTION95.92
1.72-1.750.27732380.23074508X-RAY DIFFRACTION95.47
1.75-1.770.26482300.23534386X-RAY DIFFRACTION96.11
1.77-1.80.25112370.2164503X-RAY DIFFRACTION95.8
1.8-1.830.2452350.21214463X-RAY DIFFRACTION96.41
1.83-1.860.25472360.21454478X-RAY DIFFRACTION95.99
1.86-1.90.25852340.21864439X-RAY DIFFRACTION96.69
1.9-1.930.24752380.20734536X-RAY DIFFRACTION96.21
1.93-1.970.22742350.19614457X-RAY DIFFRACTION96.8
1.97-2.020.23372360.19344484X-RAY DIFFRACTION96.86
2.02-2.060.22262380.19484518X-RAY DIFFRACTION96.71
2.06-2.110.22252360.19044481X-RAY DIFFRACTION97.16
2.11-2.170.24682390.19544556X-RAY DIFFRACTION97.22
2.17-2.240.22212390.19624530X-RAY DIFFRACTION97.27
2.24-2.310.22992370.20124512X-RAY DIFFRACTION97.58
2.31-2.390.23822390.19774537X-RAY DIFFRACTION97.65
2.39-2.490.21722380.19884522X-RAY DIFFRACTION97.78
2.49-2.60.23492420.19894590X-RAY DIFFRACTION97.91
2.6-2.740.24542390.19824543X-RAY DIFFRACTION98.09
2.74-2.910.23612410.20124584X-RAY DIFFRACTION98.35
2.91-3.130.23512410.20564576X-RAY DIFFRACTION98.53
3.13-3.450.2082400.19644572X-RAY DIFFRACTION98.65
3.45-3.940.21722430.18234605X-RAY DIFFRACTION99.02
3.94-4.970.22420.16434601X-RAY DIFFRACTION99.18
4.97-40.080.19642420.19374616X-RAY DIFFRACTION99.2
Refinement TLS params.Method: refined / Origin x: -24.3178393707 Å / Origin y: 21.6644898522 Å / Origin z: -2.200373115 Å
111213212223313233
T0.129807655879 Å20.00363434865105 Å20.00994011381007 Å2-0.162029623411 Å2-0.00124365231773 Å2--0.171601469216 Å2
L0.0114638692854 °20.0167756423913 °20.0409141348589 °2-0.0693837995499 °20.0742004040709 °2--0.228767216059 °2
S-0.00823067022972 Å °0.00501426029367 Å °-0.00318963130932 Å °0.00442656754997 Å °-0.00701958952706 Å °0.00674960577511 Å °0.0179840577023 Å °-0.00778581799448 Å °0.0130921205517 Å °
Refinement TLS groupSelection details: all

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