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- EMDB-7073: Cryo-EM structure of the pancreatic beta-cell KATP channel bound ... -

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Basic information

Entry
Database: EMDB / ID: EMD-7073
TitleCryo-EM structure of the pancreatic beta-cell KATP channel bound to ATP and glibenclamide
Map data
SamplePancreatic beta-cell ATP-sensitive K+ channel (KATP)
  • (ATP-sensitive ...) x 2
  • (ATP-binding cassette sub-family C member ...) x 2
  • (ligand) x 2
Function / homology
Function and homology information


inward rectifying potassium channel / ATP-activated inward rectifier potassium channel activity / sulfonylurea receptor activity / cell body fiber / inorganic cation transmembrane transport / ATPase-coupled cation transmembrane transporter activity / inward rectifier potassium channel activity / positive regulation of cation channel activity / potassium ion import across plasma membrane / ankyrin binding ...inward rectifying potassium channel / ATP-activated inward rectifier potassium channel activity / sulfonylurea receptor activity / cell body fiber / inorganic cation transmembrane transport / ATPase-coupled cation transmembrane transporter activity / inward rectifier potassium channel activity / positive regulation of cation channel activity / potassium ion import across plasma membrane / ankyrin binding / nervous system process / response to ATP / axolemma / potassium channel activity / intercalated disc / response to testosterone / potassium ion transmembrane transport / ATPase-coupled transmembrane transporter activity / voltage-gated potassium channel activity / regulation of ion transmembrane transport / negative regulation of insulin secretion / regulation of insulin secretion / T-tubule / acrosomal vesicle / heat shock protein binding / response to ischemia / potassium ion transport / regulation of membrane potential / cellular response to glucose stimulus / sarcolemma / positive regulation of protein localization to plasma membrane / nuclear envelope / cellular response to nicotine / glucose metabolic process / cellular response to tumor necrosis factor / myelin sheath / response to estradiol / ion channel binding / protein C-terminus binding / endosome / ATPase activity / response to drug / intracellular membrane-bounded organelle / neuronal cell body / endoplasmic reticulum / mitochondrion / integral component of membrane / ATP binding / plasma membrane / cytosol
Sulphonylurea receptor / ATP-binding cassette subfamily C member 8 / Potassium channel, inwardly rectifying, Kir6.2 / Inward rectifier potassium channel, C-terminal / Potassium channel, inwardly rectifying, transmembrane domain / ABC transporter type 1, transmembrane domain superfamily / P-loop containing nucleoside triphosphate hydrolase / ABC transporter, conserved site / Potassium channel, inwardly rectifying, Kir / Immunoglobulin E-set ...Sulphonylurea receptor / ATP-binding cassette subfamily C member 8 / Potassium channel, inwardly rectifying, Kir6.2 / Inward rectifier potassium channel, C-terminal / Potassium channel, inwardly rectifying, transmembrane domain / ABC transporter type 1, transmembrane domain superfamily / P-loop containing nucleoside triphosphate hydrolase / ABC transporter, conserved site / Potassium channel, inwardly rectifying, Kir / Immunoglobulin E-set / Potassium channel, inwardly rectifying, Kir, cytoplasmic / ABC transporter type 1, transmembrane domain / AAA+ ATPase domain / ABC transporter-like
ATP-sensitive inward rectifier potassium channel 11 / ATP-binding cassette sub-family C member 8
Biological speciesRattus norvegicus (Norway rat) / Cricetus cricetus (black-bellied hamster)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.63 Å
AuthorsMartin GM / Yoshioka C / Shyng SL
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK) United States
CitationJournal: Elife / Year: 2017
Title: Anti-diabetic drug binding site in a mammalian K channel revealed by Cryo-EM.
Authors: Gregory M Martin / Balamurugan Kandasamy / Frank DiMaio / Craig Yoshioka / Show-Ling Shyng /
Abstract: Sulfonylureas are anti-diabetic medications that act by inhibiting pancreatic K channels composed of SUR1 and Kir6.2. The mechanism by which these drugs interact with and inhibit the channel has been ...Sulfonylureas are anti-diabetic medications that act by inhibiting pancreatic K channels composed of SUR1 and Kir6.2. The mechanism by which these drugs interact with and inhibit the channel has been extensively investigated, yet it remains unclear where the drug binding pocket resides. Here, we present a cryo-EM structure of a hamster SUR1/rat Kir6.2 channel bound to a high-affinity sulfonylurea drug glibenclamide and ATP at 3.63 Å resolution, which reveals unprecedented details of the ATP and glibenclamide binding sites. Importantly, the structure shows for the first time that glibenclamide is lodged in the transmembrane bundle of the SUR1-ABC core connected to the first nucleotide binding domain near the inner leaflet of the lipid bilayer. Mutation of residues predicted to interact with glibenclamide in our model led to reduced sensitivity to glibenclamide. Our structure provides novel mechanistic insights of how sulfonylureas and ATP interact with the K channel complex to inhibit channel activity.
Validation ReportPDB-ID: 6baa

SummaryFull reportAbout validation report
History
DepositionOct 12, 2017-
Header (metadata) releaseNov 1, 2017-
Map releaseNov 1, 2017-
UpdateDec 25, 2019-
Current statusDec 25, 2019Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 5
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 5
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6baa
  • Surface level: 5
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

FileDownload / File: emd_7073.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.86 Å/pix.
x 300 pix.
= 256.5 Å
0.86 Å/pix.
x 300 pix.
= 256.5 Å
0.86 Å/pix.
x 300 pix.
= 256.5 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.855 Å
Density
Contour LevelBy AUTHOR: 5 / Movie #1: 5
Minimum - Maximum-9.947775 - 21.047916
Average (Standard dev.)0.16722862 (±1.3686122)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 256.5 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.8550.8550.855
M x/y/z300300300
origin x/y/z0.0000.0000.000
length x/y/z256.500256.500256.500
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS300300300
D min/max/mean-9.94821.0480.167

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Supplemental data

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Segmentation: #1

Fileemd_7073_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Additional map: unsharpened; unfiltered map of pancreatic beta-cell KATP channel...

Fileemd_7073_additional.map
Annotationunsharpened; unfiltered map of pancreatic beta-cell KATP channel bound to ATP and glibenclamide
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Sample components

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Entire Pancreatic beta-cell ATP-sensitive K+ channel (KATP)

EntireName: Pancreatic beta-cell ATP-sensitive K+ channel (KATP) / Number of components: 7

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Component #1: protein, Pancreatic beta-cell ATP-sensitive K+ channel (KATP)

ProteinName: Pancreatic beta-cell ATP-sensitive K+ channel (KATP) / Recombinant expression: No
MassTheoretical: 950 kDa
SourceSpecies: Rattus norvegicus (Norway rat)
Source (engineered)Expression System: Rattus norvegicus (Norway rat)

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Component #2: protein, ATP-sensitive K+ channel subunit Kir6.2

ProteinName: ATP-sensitive K+ channel subunit Kir6.2 / Recombinant expression: No

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Component #3: protein, ATP-binding cassette sub-family C member 8

ProteinName: ATP-binding cassette sub-family C member 8 / Recombinant expression: No

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Component #4: protein, ATP-sensitive inward rectifier potassium channel 11

ProteinName: ATP-sensitive inward rectifier potassium channel 11 / Number of Copies: 4 / Recombinant expression: No
MassTheoretical: 43.645719 kDa
SourceSpecies: Rattus norvegicus (Norway rat)
Source (engineered)Expression System: Rattus norvegicus (Norway rat)

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Component #5: protein, ATP-binding cassette sub-family C member 8

ProteinName: ATP-binding cassette sub-family C member 8 / Number of Copies: 4 / Recombinant expression: No
MassTheoretical: 177.333578 kDa
SourceSpecies: Cricetus cricetus (black-bellied hamster)
Source (engineered)Expression System: Rattus norvegicus (Norway rat)

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Component #6: ligand, ADENOSINE-5'-TRIPHOSPHATE

LigandName: ADENOSINE-5'-TRIPHOSPHATE / Number of Copies: 4 / Recombinant expression: No
MassTheoretical: 0.507181 kDa

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Component #7: ligand, 5-chloro-N-(2-{4-[(cyclohexylcarbamoyl)sulfamoyl]phenyl}e...

LigandName: 5-chloro-N-(2-{4-[(cyclohexylcarbamoyl)sulfamoyl]phenyl}ethyl)-2-methoxybenzamide
Number of Copies: 4 / Recombinant expression: No
MassTheoretical: 0.494004 kDa

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Experimental details

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Sample preparation

SpecimenSpecimen state: Particle / Method: cryo EM
Sample solutionpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
ImagingMicroscope: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Electron dose: 40 e/Å2 / Illumination mode: FLOOD BEAM
LensImaging mode: BRIGHT FIELD
Specimen HolderModel: OTHER
CameraDetector: GATAN K2 SUMMIT (4k x 4k)

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Image processing

ProcessingMethod: single particle reconstruction / Applied symmetry: C4 (4 fold cyclic) / Number of projections: 59417
3D reconstructionResolution: 3.63 Å / Resolution method: FSC 0.143 CUT-OFF

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Atomic model buiding

Output model

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