+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-23614 | ||||||||||||
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Title | SN-407-LRRC8A in MSP1E3D1 lipid nanodiscs (Pose-1) | ||||||||||||
Map data | SN-407-LRRC8A in MSP1E3D1 lipid nanodiscs (Pose-1) | ||||||||||||
Sample |
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Function / homology | Function and homology information Miscellaneous transport and binding events / pre-B cell differentiation / volume-sensitive anion channel activity / taurine transmembrane transport / aspartate transmembrane transport / cyclic-GMP-AMP transmembrane transporter activity / cyclic-GMP-AMP transmembrane import across plasma membrane / monoatomic anion transmembrane transport / cell volume homeostasis / protein hexamerization ...Miscellaneous transport and binding events / pre-B cell differentiation / volume-sensitive anion channel activity / taurine transmembrane transport / aspartate transmembrane transport / cyclic-GMP-AMP transmembrane transporter activity / cyclic-GMP-AMP transmembrane import across plasma membrane / monoatomic anion transmembrane transport / cell volume homeostasis / protein hexamerization / monoatomic anion transport / 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 / identical protein binding / plasma membrane / cytoplasm Similarity search - Function | ||||||||||||
Biological species | Mus musculus (house mouse) | ||||||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.65 Å | ||||||||||||
Authors | Kern DM / Gerber EE / Brohawn SG | ||||||||||||
Funding support | United States, 3 items
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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 SK / Xie L / Chheda PR / Kang C / Kern DM / My-Ta C / Kumar A / Maurer J / Gerber EE / Grzesik WJ / Elliot-Hudson M / Zhang Y / Kulkarni CA / Samuel I / Smith JK / Nau P / Imai Y / ...Authors: Gunasekar SK / Xie L / Chheda PR / Kang C / Kern DM / My-Ta C / Kumar A / Maurer J / Gerber EE / Grzesik WJ / Elliot-Hudson M / Zhang Y / Kulkarni CA / Samuel I / Smith JK / Nau P / Imai Y / Sheldon RD / Taylor EB / Lerner DJ / Norris AW / Brohawn SG / Kerns R / Sah R | ||||||||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_23614.map.gz | 141 MB | EMDB map data format | |
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Header (meta data) | emd-23614-v30.xml emd-23614.xml | 21.4 KB 21.4 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_23614_fsc.xml | 12.8 KB | Display | FSC data file |
Images | emd_23614.png | 296.3 KB | ||
Masks | emd_23614_msk_1.map | 178 MB | Mask map | |
Others | emd_23614_half_map_1.map.gz emd_23614_half_map_2.map.gz | 141.2 MB 140.9 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-23614 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-23614 | HTTPS FTP |
-Validation report
Summary document | emd_23614_validation.pdf.gz | 823 KB | Display | EMDB validaton report |
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Full document | emd_23614_full_validation.pdf.gz | 822.5 KB | Display | |
Data in XML | emd_23614_validation.xml.gz | 20 KB | Display | |
Data in CIF | emd_23614_validation.cif.gz | 26.6 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-23614 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-23614 | HTTPS FTP |
-Related structure data
Related structure data | 7m17MC 7m19C M: atomic model generated by this map 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
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_23614.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Annotation | SN-407-LRRC8A in MSP1E3D1 lipid nanodiscs (Pose-1) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.137 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Mask #1
File | emd_23614_msk_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: half-volume 1
File | emd_23614_half_map_1.map | ||||||||||||
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Annotation | half-volume 1 | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: half-volume 2
File | emd_23614_half_map_2.map | ||||||||||||
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Annotation | half-volume 2 | ||||||||||||
Projections & Slices |
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Density Histograms |
-Sample components
-Entire : SN407-LRRC8A in MSP1E3D1 lipid nanodiscs (Pose-1)
Entire | Name: SN407-LRRC8A in MSP1E3D1 lipid nanodiscs (Pose-1) |
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Components |
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-Supramolecule #1: SN407-LRRC8A in MSP1E3D1 lipid nanodiscs (Pose-1)
Supramolecule | Name: SN407-LRRC8A in MSP1E3D1 lipid nanodiscs (Pose-1) / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: Mus musculus (house mouse) |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) / Recombinant cell: Sf9 |
-Macromolecule #1: Volume-regulated anion channel subunit LRRC8A
Macromolecule | Name: Volume-regulated anion channel subunit LRRC8A / type: protein_or_peptide / ID: 1 / Number of copies: 6 / Enantiomer: LEVO |
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Source (natural) | Organism: Mus musculus (house mouse) |
Molecular weight | Theoretical: 95.257508 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: MIPVTELRYF ADTQPAYRIL KPWWDVFTDY ISIVMLMIAV FGGTLQVTQD KMICLPCKWV TKDSCNDSFR GWAASSPEPT YPNSTVLPT PDTGPTGIKY DLDRHQYNYV DAVCYENRLH WFAKYFPYLV LLHTLIFLAC SNFWFKFPRT SSKLEHFVSI L LKCFDSPW ...String: MIPVTELRYF ADTQPAYRIL KPWWDVFTDY ISIVMLMIAV FGGTLQVTQD KMICLPCKWV TKDSCNDSFR GWAASSPEPT YPNSTVLPT PDTGPTGIKY DLDRHQYNYV DAVCYENRLH WFAKYFPYLV LLHTLIFLAC SNFWFKFPRT SSKLEHFVSI L LKCFDSPW TTRALSETVV EESDPKPAFS KMNGSMDKKS STVSEDVEAT VPMLQRTKSR IEQGIVDRSE TGVLDKKEGE QA KALFEKV KKFRTHVEEG DIVYRLYMRQ TIIKVIKFAL IICYTVYYVH NIKFDVDCTV DIESLTGYRT YRCAHPLATL FKI LASFYI SLVIFYGLIC MYTLWWMLRR SLKKYSFESI REESSYSDIP DVKNDFAFML HLIDQYDPLY SKRFAVFLSE VSEN KLRQL NLNNEWTLDK LRQRLTKNAQ DKLELHLFML SGIPDTVFDL VELEVLKLEL IPDVTIPPSI AQLTGLKELW LYHTA AKIE APALAFLREN LRALHIKFTD IKEIPLWIYS LKTLEELHLT GNLSAENNRY IVIDGLRELK RLKVLRLKSN LSKLPQ VVT DVGVHLQKLS INNEGTKLIV LNSLKKMVNL TELELIRCDL ERIPHSIFSL HNLQEIDLKD NNLKTIEEII SFQHLHR LT CLKLWYNHIA YIPIQIGNLT NLERLYLNRN KIEKIPTQLF YCRKLRYLDL SHNNLTFLPA DIGLLQNLQN LAVTANRI E ALPPELFQCR KLRALHLGNN VLQSLPSRVG ELTNLTQIEL RGNRLECLPV ELGECPLLKR SGLVVEEDLF STLPPEVKE RLWRADKEQA SNSLEVLFQ |
-Macromolecule #2: 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine
Macromolecule | Name: 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine / type: ligand / ID: 2 / Number of copies: 18 / Formula: PEE |
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Molecular weight | Theoretical: 744.034 Da |
Chemical component information | ChemComp-PEE: |
-Macromolecule #3: 7-{[(2S)-2-butyl-6,7-dichloro-2-cyclopentyl-1-oxo-2,3-dihydro-1H-...
Macromolecule | Name: 7-{[(2S)-2-butyl-6,7-dichloro-2-cyclopentyl-1-oxo-2,3-dihydro-1H-inden-5-yl]oxy}heptanoic acid type: ligand / ID: 3 / Number of copies: 1 / Formula: YNJ |
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Molecular weight | Theoretical: 469.441 Da |
Chemical component information | ChemComp-YNJ: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 1 mg/mL | |||||||||
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Buffer | pH: 7.4 Component:
Details: pH to 7.4 with KOH | |||||||||
Grid | Model: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Support film - Film thickness: 12.0 nm | |||||||||
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 295.15 K / Instrument: FEI VITROBOT MARK IV Details: 2 microliter drop size, manual wait time of 2 seconds, blot force of 1, 3 second blot time. |
-Electron microscopy
Microscope | FEI TALOS ARCTICA |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 51.59 e/Å2 |
Electron beam | Acceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD |
Experimental equipment | Model: Talos Arctica / Image courtesy: FEI Company |