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- EMDB-23616: SN-407-LRRC8A in MSP1E3D1 lipid nanodiscs (Pose-2) -

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Basic information

Entry
Database: EMDB / ID: EMD-23616
TitleSN-407-LRRC8A in MSP1E3D1 lipid nanodiscs (Pose-2)
Map dataSN-407-LRRC8A in MSP1E3D1 lipid nanodiscs (Pose-2)
Sample
  • Complex: SN407-LRRC8A in MSP1E3D1 lipid nanodiscs (Pose-2)
    • Protein or peptide: Volume-regulated anion channel subunit LRRC8A
  • Ligand: 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine
  • Ligand: 7-{[(2S)-2-butyl-6,7-dichloro-2-cyclopentyl-1-oxo-2,3-dihydro-1H-inden-5-yl]oxy}heptanoic acid
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
Volume-regulated anion channel subunit LRRC8A
Similarity search - Component
Biological speciesMus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.69 Å
AuthorsKern DM / Gerber EE / Brohawn SG
Funding support United States, 3 items
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 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
DepositionMar 12, 2021-
Header (metadata) releaseMar 24, 2021-
Map releaseMar 24, 2021-
UpdateFeb 23, 2022-
Current statusFeb 23, 2022Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.013
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.013
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  • Surface view with fitted model
  • Atomic models: PDB-7m19
  • Surface level: 0.013
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7m19
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_23616.png

Downloads & links

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Map

FileDownload / File: emd_23616.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSN-407-LRRC8A in MSP1E3D1 lipid nanodiscs (Pose-2)
Voxel sizeX=Y=Z: 1.137 Å
Density
Contour LevelBy AUTHOR: 0.008 / Movie #1: 0.013
Minimum - Maximum-0.039576277 - 0.121268645
Average (Standard dev.)1.7752463e-05 (±0.0015966721)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 409.31998 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.1371.1371.137
M x/y/z360360360
origin x/y/z0.0000.0000.000
length x/y/z409.320409.320409.320
α/β/γ90.00090.00090.000
start NX/NY/NZ1219875
NX/NY/NZ141223232
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS360360360
D min/max/mean-0.0400.1210.000

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Supplemental data

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Mask #1

Fileemd_23616_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half-volume 1

Fileemd_23616_half_map_1.map
Annotationhalf-volume 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half-volume 2

Fileemd_23616_half_map_2.map
Annotationhalf-volume 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : SN407-LRRC8A in MSP1E3D1 lipid nanodiscs (Pose-2)

EntireName: SN407-LRRC8A in MSP1E3D1 lipid nanodiscs (Pose-2)
Components
  • Complex: SN407-LRRC8A in MSP1E3D1 lipid nanodiscs (Pose-2)
    • Protein or peptide: Volume-regulated anion channel subunit LRRC8A
  • Ligand: 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine
  • Ligand: 7-{[(2S)-2-butyl-6,7-dichloro-2-cyclopentyl-1-oxo-2,3-dihydro-1H-inden-5-yl]oxy}heptanoic acid

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Supramolecule #1: SN407-LRRC8A in MSP1E3D1 lipid nanodiscs (Pose-2)

SupramoleculeName: SN407-LRRC8A in MSP1E3D1 lipid nanodiscs (Pose-2) / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Mus musculus (house mouse)
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm) / Recombinant cell: Sf9

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Macromolecule #1: Volume-regulated anion channel subunit LRRC8A

MacromoleculeName: Volume-regulated anion channel subunit LRRC8A / type: protein_or_peptide / ID: 1 / Number of copies: 6 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 95.257508 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: 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

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Macromolecule #2: 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine

MacromoleculeName: 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine / type: ligand / ID: 2 / Number of copies: 18 / Formula: PEE
Molecular weightTheoretical: 744.034 Da
Chemical component information

ChemComp-PEE:
1,2-dioleoyl-sn-glycero-3-phosphoethanolamine / DOPE, phospholipid*YM / Discrete optimized protein energy

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Macromolecule #3: 7-{[(2S)-2-butyl-6,7-dichloro-2-cyclopentyl-1-oxo-2,3-dihydro-1H-...

MacromoleculeName: 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
Molecular weightTheoretical: 469.441 Da
Chemical component information

ChemComp-YNJ:
7-{[(2S)-2-butyl-6,7-dichloro-2-cyclopentyl-1-oxo-2,3-dihydro-1H-inden-5-yl]oxy}heptanoic acid

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration1 mg/mL
BufferpH: 7.4
Component:
ConcentrationFormulaName
20.0 mMC8H18N2O4SHEPES
150.0 mMKClPotassium Chloride

Details: pH to 7.4 with KOH
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Support film - Film thickness: 12.0 nm
VitrificationCryogen 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.

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 51.59 e/Å2
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: CTFFIND (ver. 4.1)
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.69 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1) / Number images used: 78324
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

6nzw

Output model

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

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