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- PDB-9t5r: LRR domain structure of the LRRC8D protein -

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Basic information

Entry
Database: PDB / ID: 9t5r
TitleLRR domain structure of the LRRC8D protein
ComponentsVolume-regulated anion channel subunit LRRC8D
KeywordsCYTOSOLIC PROTEIN / Cytosolic domain of LRRC8D
Function / homology
Function and homology information


Miscellaneous transport and binding events / volume-sensitive anion channel activity / aspartate transmembrane transport / monoatomic anion transmembrane transport / taurine transmembrane transport / monoatomic ion channel complex / cellular response to osmotic stress / protein hexamerization / intracellular glucose homeostasis / endoplasmic reticulum membrane ...Miscellaneous transport and binding events / volume-sensitive anion channel activity / aspartate transmembrane transport / monoatomic anion transmembrane transport / taurine transmembrane transport / monoatomic ion channel complex / cellular response to osmotic stress / protein hexamerization / intracellular glucose homeostasis / endoplasmic reticulum membrane / membrane / plasma membrane / cytoplasm
Similarity search - Function
LRRC8, pannexin-like TM region / Pannexin-like TM region of LRRC8 / : / 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
S,S-(2-HYDROXYETHYL)THIOCYSTEINE / Volume-regulated anion channel subunit LRRC8D
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.96 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 LRRC8D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,2022
Polymers47,0051
Non-polymers1971
Water5,873326
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area19010 Å2
Unit cell
Length a, b, c (Å)36.855, 89.535, 143.698
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

#1: Protein Volume-regulated anion channel subunit LRRC8D / Leucine-rich repeat-containing protein 5 / Leucine-rich repeat-containing protein 8D


Mass: 47004.785 Da / Num. of mol.: 1
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
#2: Chemical ChemComp-CME / S,S-(2-HYDROXYETHYL)THIOCYSTEINE


Type: L-peptide linking / Mass: 197.276 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H11NO3S2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 326 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.51 Å3/Da / Density % sol: 51.04 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop / Details: 0.2 M malonate and 20% (w/v) PEG 3350

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Data collection

DiffractionMean temperature: 80 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Feb 23, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.96→44.8 Å / Num. obs: 63729 / % possible obs: 96.35 % / Redundancy: 26.1 % / Biso Wilson estimate: 38.38 Å2 / Rmerge(I) obs: 9.8 / Net I/σ(I): 22.43
Reflection shellResolution: 1.96→1.99 Å / Rmerge(I) obs: 9.8 / Num. unique obs: 34115

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Processing

Software
NameVersionClassification
PHENIX1.21.2_5419+SVNrefinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.96→44.77 Å / SU ML: 0.3005 / Cross valid method: FREE R-VALUE / σ(F): 1.17 / Phase error: 26.1183
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2263 3200 5.02 %
Rwork0.1936 60529 -
obs0.1952 63729 96.34 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 45.32 Å2
Refinement stepCycle: LAST / Resolution: 1.96→44.77 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3267 0 0 326 3593
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0073374
X-RAY DIFFRACTIONf_angle_d0.8464567
X-RAY DIFFRACTIONf_chiral_restr0.0524548
X-RAY DIFFRACTIONf_plane_restr0.0054578
X-RAY DIFFRACTIONf_dihedral_angle_d17.39361298
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.96-1.990.49821410.43152681X-RAY DIFFRACTION98.43
1.99-2.020.31581470.32652772X-RAY DIFFRACTION100
2.02-2.050.29961410.29432736X-RAY DIFFRACTION99.97
2.05-2.090.28511410.27932699X-RAY DIFFRACTION99.68
2.09-2.120.28871420.23252719X-RAY DIFFRACTION100
2.12-2.170.26911440.23272783X-RAY DIFFRACTION100
2.17-2.210.26211420.24712677X-RAY DIFFRACTION100
2.21-2.260.6032660.51681210X-RAY DIFFRACTION44.76
2.26-2.310.34941200.29712213X-RAY DIFFRACTION80.42
2.31-2.370.2331430.21872676X-RAY DIFFRACTION100
2.37-2.430.23851490.19942751X-RAY DIFFRACTION100
2.43-2.50.2221400.19572720X-RAY DIFFRACTION100
2.5-2.580.22711460.19272713X-RAY DIFFRACTION99.93
2.58-2.680.25771470.20222758X-RAY DIFFRACTION99.79
2.68-2.780.24461460.19192695X-RAY DIFFRACTION99.41
2.78-2.910.24841380.20892713X-RAY DIFFRACTION100
2.91-3.060.25781490.2152780X-RAY DIFFRACTION100
3.06-3.260.2251420.20062687X-RAY DIFFRACTION100
3.26-3.510.23141420.19082726X-RAY DIFFRACTION99.97
3.51-3.860.25681430.1832675X-RAY DIFFRACTION97.24
3.86-4.420.15121440.14332690X-RAY DIFFRACTION99.09
4.42-5.570.16921460.14472722X-RAY DIFFRACTION99.38
5.57-44.770.18231410.16152733X-RAY DIFFRACTION99.79
Refinement TLS params.Method: refined / Origin x: 12.9775567688 Å / Origin y: -19.8341581707 Å / Origin z: -33.4026580496 Å
111213212223313233
T0.253834248571 Å2-0.0217273297547 Å2-0.0606337347928 Å2-0.269124433307 Å2-0.00599660494532 Å2--0.315362004743 Å2
L0.380708074901 °20.185715210401 °2-0.308302203277 °2-0.966822982951 °2-0.511226911286 °2--1.2573375505 °2
S-0.079829210908 Å °-0.0371828488916 Å °0.00106692457801 Å °-0.218335420781 Å °0.0199352864893 Å °0.0224574726352 Å °0.0751561679247 Å °0.0978288850896 Å °0.0537568109267 Å °
Refinement TLS groupSelection details: all

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