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- PDB-7m19: SN-407-LRRC8A in MSP1E3D1 lipid nanodiscs (Pose-2) -

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Basic information

Entry
Database: PDB / ID: 7m19
TitleSN-407-LRRC8A in MSP1E3D1 lipid nanodiscs (Pose-2)
ComponentsVolume-regulated anion channel subunit LRRC8A
KeywordsMEMBRANE PROTEIN / Ion channel / Inhibitor
Function / homology
Function and homology information


Miscellaneous transport and binding events / pre-B cell differentiation / volume-sensitive anion channel activity / taurine transmembrane transport / monoatomic anion transmembrane transport / aspartate transmembrane transport / cyclic-GMP-AMP transmembrane transporter activity / cyclic-GMP-AMP transmembrane import across plasma membrane / monoatomic anion transport / cell volume homeostasis ...Miscellaneous transport and binding events / pre-B cell differentiation / volume-sensitive anion channel activity / taurine transmembrane transport / monoatomic anion transmembrane transport / aspartate transmembrane transport / cyclic-GMP-AMP transmembrane transporter activity / cyclic-GMP-AMP transmembrane import across plasma membrane / monoatomic anion transport / cell volume homeostasis / protein hexamerization / response to osmotic stress / monoatomic ion channel complex / intracellular glucose homeostasis / positive regulation of myoblast differentiation / chloride transmembrane transport / positive regulation of insulin secretion / spermatogenesis / lysosomal membrane / cell surface / signal transduction / membrane / identical protein binding / plasma membrane
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
1,2-dioleoyl-sn-glycero-3-phosphoethanolamine / Chem-YNJ / Volume-regulated anion channel subunit LRRC8A
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.69 Å
AuthorsKern, D.M. / Gerber, E.E. / Brohawn, S.G.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)F32GM128263 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)DP2GM123496 United States
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)1R01DK106009 United States
Citation
Journal: Nat Commun / Year: 2022
Title: Small molecule SWELL1 complex induction improves glycemic control and nonalcoholic fatty liver disease in murine Type 2 diabetes.
Authors: Susheel K Gunasekar / Litao Xie / Ashutosh Kumar / Juan Hong / Pratik R Chheda / Chen Kang / David M Kern / Chau My-Ta / Joshua Maurer / John Heebink / Eva E Gerber / Wojciech J Grzesik / ...Authors: Susheel K Gunasekar / Litao Xie / Ashutosh Kumar / Juan Hong / Pratik R Chheda / Chen Kang / David M Kern / Chau My-Ta / Joshua Maurer / John Heebink / Eva E Gerber / Wojciech J Grzesik / Macaulay Elliot-Hudson / Yanhui Zhang / Phillip Key / Chaitanya A Kulkarni / Joseph W Beals / Gordon I Smith / Isaac Samuel / Jessica K Smith / Peter Nau / Yumi Imai / Ryan D Sheldon / Eric B Taylor / Daniel J Lerner / Andrew W Norris / Samuel Klein / Stephen G Brohawn / Robert Kerns / Rajan Sah /
Abstract: Type 2 diabetes is associated with insulin resistance, impaired pancreatic β-cell insulin secretion, and nonalcoholic fatty liver disease. Tissue-specific SWELL1 ablation impairs insulin signaling ...Type 2 diabetes is associated with insulin resistance, impaired pancreatic β-cell insulin secretion, and nonalcoholic fatty liver disease. Tissue-specific SWELL1 ablation impairs insulin signaling in adipose, skeletal muscle, and endothelium, and impairs β-cell insulin secretion and glycemic control. Here, we show that I and SWELL1 protein are reduced in adipose and β-cells in murine and human diabetes. Combining cryo-electron microscopy, molecular docking, medicinal chemistry, and functional studies, we define a structure activity relationship to rationally-design active derivatives of a SWELL1 channel inhibitor (DCPIB/SN-401), that bind the SWELL1 hexameric complex, restore SWELL1 protein, plasma membrane trafficking, signaling, glycemic control and islet insulin secretion via SWELL1-dependent mechanisms. In vivo, SN-401 restores glycemic control, reduces hepatic steatosis/injury, improves insulin-sensitivity and insulin secretion in murine diabetes. These findings demonstrate that SWELL1 channel modulators improve SWELL1-dependent systemic metabolism in Type 2 diabetes, representing a first-in-class therapeutic approach for diabetes and nonalcoholic fatty liver disease.
#1: Journal: biorxiv / Year: 2021
Title: Small molecule SWELL1-LRRC8 complex induction improves glycemic control and nonalcoholic fatty liver disease in murine Type 2 diabetes
Authors: Gunasekar, S.K. / Xie, L. / Chheda, P.R. / Kang, C. / Kern, D.M. / My-Ta, C. / Kumar, A. / Maurer, J. / Gerber, E.E. / Grzesik, W.J. / Elliot-Hudson, M. / Zhang, Y. / Kulkarni, C.A. / ...Authors: Gunasekar, S.K. / Xie, L. / Chheda, P.R. / Kang, C. / Kern, D.M. / My-Ta, C. / Kumar, A. / Maurer, J. / Gerber, E.E. / Grzesik, W.J. / Elliot-Hudson, M. / Zhang, Y. / Kulkarni, C.A. / Samuel, I. / Smith, J.K. / Nau, P. / Imai, Y. / Sheldon, R.D. / Taylor, E.B. / Lerner, D.J. / Norris, A.W. / Brohawn, S.G. / Kerns, R. / Sah, R.
History
DepositionMar 12, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 24, 2021Provider: repository / Type: Initial release
Revision 2.0Sep 29, 2021Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Database references / Derived calculations / Non-polymer description / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / database_2 / entity / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_unobs_or_zero_occ_atoms
Item: _atom_site.auth_atom_id / _atom_site.auth_comp_id ..._atom_site.auth_atom_id / _atom_site.auth_comp_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _chem_comp.formula / _chem_comp.formula_weight / _chem_comp.id / _chem_comp.mon_nstd_flag / _chem_comp.name / _chem_comp.pdbx_synonyms / _chem_comp.type / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.pdbx_description / _pdbx_entity_nonpoly.comp_id / _pdbx_entity_nonpoly.name / _pdbx_nonpoly_scheme.mon_id / _pdbx_nonpoly_scheme.pdb_mon_id / _pdbx_unobs_or_zero_occ_atoms.auth_atom_id / _pdbx_unobs_or_zero_occ_atoms.auth_comp_id / _pdbx_unobs_or_zero_occ_atoms.label_atom_id / _pdbx_unobs_or_zero_occ_atoms.label_comp_id
Revision 2.1Feb 23, 2022Group: Database references / Category: citation / citation_author

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Structure visualization

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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
E: Volume-regulated anion channel subunit LRRC8A
F: Volume-regulated anion channel subunit LRRC8A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)585,40725
Polymers571,5456
Non-polymers13,86219
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Volume-regulated anion channel subunit LRRC8A / / Leucine-rich repeat-containing protein 8A


Mass: 95257.508 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Lrrc8a, Lrrc8 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q80WG5
#2: Chemical
ChemComp-PEE / 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine / DOPE / Discrete optimized protein energy


Mass: 744.034 Da / Num. of mol.: 18 / Source method: obtained synthetically / Formula: C41H78NO8P / Comment: DOPE, phospholipid*YM
#3: Chemical ChemComp-YNJ / 7-{[(2S)-2-butyl-6,7-dichloro-2-cyclopentyl-1-oxo-2,3-dihydro-1H-inden-5-yl]oxy}heptanoic acid


Mass: 469.441 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H34Cl2O4 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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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: SN407-LRRC8A in MSP1E3D1 lipid nanodiscs (Pose-2) / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightUnits: KILODALTONS/NANOMETER / Experimental value: NO
Source (natural)Organism: Mus musculus (house mouse)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm) / Cell: Sf9
Buffer solutionpH: 7.4 / Details: pH to 7.4 with KOH
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMHEPESC8H18N2O4S1
2150 mMPotassium ChlorideKCl1
SpecimenConc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 295.15 K
Details: 2 microliter drop size, manual wait time of 2 seconds, blot force of 1, 3 second blot time

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 51.59 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

Software
NameVersionClassificationNB
phenix.real_space_refine1.18.2_3874refinement
PHENIX1.18.2_3874refinement
EM software
IDNameVersionCategory
2SerialEMimage acquisition
4CTFFIND4.1CTF correction
7Cootmodel fitting
9PHENIX1.18.2model refinement
13RELION3.13D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.69 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 78324 / Symmetry type: POINT
Atomic model buildingPDB-ID: 6NZW

6nzw

RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 124.17 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.004216473
ELECTRON MICROSCOPYf_angle_d0.84722222
ELECTRON MICROSCOPYf_chiral_restr0.05122408
ELECTRON MICROSCOPYf_plane_restr0.00472679
ELECTRON MICROSCOPYf_dihedral_angle_d25.67782272

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