+Open data
-Basic information
Entry | Database: PDB / ID: 7m17 | ||||||||||||
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Title | SN-407-LRRC8A in MSP1E3D1 lipid nanodiscs (Pose-1) | ||||||||||||
Components | Volume-regulated anion channel subunit LRRC8A | ||||||||||||
Keywords | MEMBRANE 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 | ||||||||||||
Biological species | Mus musculus (house mouse) | ||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.65 Å | ||||||||||||
Authors | Kern, D.M. / Gerber, E.E. / Brohawn, S.G. | ||||||||||||
Funding support | United States, 3items
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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 |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | Molecule: MolmilJmol/JSmol |
-Downloads & links
-Download
PDBx/mmCIF format | 7m17.cif.gz | 399.9 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7m17.ent.gz | 309.9 KB | Display | PDB format |
PDBx/mmJSON format | 7m17.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/m1/7m17 ftp://data.pdbj.org/pub/pdb/validation_reports/m1/7m17 | HTTPS FTP |
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-Related structure data
Related structure data | 23614MC 7m19C M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | |
EM raw data | EMPIAR-10662 (Title: SN-407-LRRC8A in MSP1E3D1 lipid nanodiscs / Data size: 2.7 TB Data #1: LRRC8A-SN-407 in MSP1E3D1 nanodiscs [micrographs - multiframe]) |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
#1: Protein | 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 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q80WG5 #2: Chemical | ChemComp-PEE / #3: Chemical | ChemComp-YNJ / | Has ligand of interest | Y | |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: SN407-LRRC8A in MSP1E3D1 lipid nanodiscs (Pose-1) / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT | |||||||||||||||
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Molecular weight | Units: KILODALTONS/NANOMETER / Experimental value: NO | |||||||||||||||
Source (natural) | Organism: Mus musculus (house mouse) | |||||||||||||||
Source (recombinant) | Organism: Spodoptera frugiperda (fall armyworm) / Cell: Sf9 | |||||||||||||||
Buffer solution | pH: 7.4 / Details: pH to 7.4 with KOH | |||||||||||||||
Buffer component |
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Specimen | Conc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | |||||||||||||||
Specimen support | Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3 | |||||||||||||||
Vitrification | Instrument: 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 |
-Electron microscopy imaging
Experimental equipment | Model: Talos Arctica / Image courtesy: FEI Company |
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Microscopy | Model: FEI TALOS ARCTICA |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELDBright-field microscopy |
Image recording | Electron dose: 51.59 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
-Processing
Software |
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EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
Symmetry | Point symmetry: C1 (asymmetric) | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.65 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 85831 / Symmetry type: POINT | ||||||||||||||||||||||||
Atomic model building | PDB-ID: 6NZW | ||||||||||||||||||||||||
Refinement | Cross valid method: NONE Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2 | ||||||||||||||||||||||||
Displacement parameters | Biso mean: 129.63 Å2 | ||||||||||||||||||||||||
Refine LS restraints |
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