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- EMDB-20534: Cryo-EM structure of the pancreatic beta-cell SUR1 bound to carba... -

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Basic information

Entry
Database: EMDB / ID: EMD-20534
TitleCryo-EM structure of the pancreatic beta-cell SUR1 bound to carbamazepine
Map data
SampleSUR1ABCC8
  • ATP-binding cassette sub-family C member 8
Function / homology
Function and homology information


sulfonylurea receptor activity / potassium channel activity / ATPase-coupled transmembrane transporter activity / ATPase activity / integral component of membrane / ATP binding / plasma membrane
AAA+ ATPase domain / ABC transporter type 1, transmembrane domain superfamily / ABC transporter integral membrane type-1 fused domain profile. / ATP-binding cassette, ABC transporter-type domain profile. / ABC transporters family signature. / ABC transporter transmembrane region / Sulphonylurea receptor / ATP-binding cassette subfamily C member 8 / ABC transporter-like / ABC transporter ...AAA+ ATPase domain / ABC transporter type 1, transmembrane domain superfamily / ABC transporter integral membrane type-1 fused domain profile. / ATP-binding cassette, ABC transporter-type domain profile. / ABC transporters family signature. / ABC transporter transmembrane region / Sulphonylurea receptor / ATP-binding cassette subfamily C member 8 / ABC transporter-like / ABC transporter / ABC transporter type 1, transmembrane domain / ABC transporter, conserved site / P-loop containing nucleoside triphosphate hydrolase
ATP-binding cassette sub-family C member 8
Biological speciesCricetus cricetus (black-bellied hamster)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.34 Å
AuthorsShyng SL / Yoshioka C / Martin GM / Sung MW
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease United States
CitationJournal: Elife / Year: 2019
Title: Mechanism of pharmacochaperoning in a mammalian K channel revealed by cryo-EM.
Authors: Gregory M Martin / Min Woo Sung / Zhongying Yang / Laura M Innes / Balamurugan Kandasamy / Larry L David / Craig Yoshioka / Show-Ling Shyng /
Abstract: ATP-sensitive potassium (K) channels composed of a pore-forming Kir6.2 potassium channel and a regulatory ABC transporter sulfonylurea receptor 1 (SUR1) regulate insulin secretion in pancreatic ...ATP-sensitive potassium (K) channels composed of a pore-forming Kir6.2 potassium channel and a regulatory ABC transporter sulfonylurea receptor 1 (SUR1) regulate insulin secretion in pancreatic β-cells to maintain glucose homeostasis. Mutations that impair channel folding or assembly prevent cell surface expression and cause congenital hyperinsulinism. Structurally diverse K inhibitors are known to act as pharmacochaperones to correct mutant channel expression, but the mechanism is unknown. Here, we compare cryoEM structures of a mammalian K channel bound to pharmacochaperones glibenclamide, repaglinide, and carbamazepine. We found all three drugs bind within a common pocket in SUR1. Further, we found the N-terminus of Kir6.2 inserted within the central cavity of the SUR1 ABC core, adjacent the drug binding pocket. The findings reveal a common mechanism by which diverse compounds stabilize the Kir6.2 N-terminus within SUR1's ABC core, allowing it to act as a firm 'handle' for the assembly of metastable mutant SUR1-Kir6.2 complexes.
Validation ReportPDB-ID: 6pzc

SummaryFull reportAbout validation report
History
DepositionJul 31, 2019-
Header (metadata) releaseAug 14, 2019-
Map releaseAug 14, 2019-
UpdateAug 14, 2019-
Current statusAug 14, 2019Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.0366
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.0366
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: : PDB-6pzc
  • Surface level: 0.0366
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic models: PDB-6pzc
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

FileDownload / File: emd_20534.map.gz / Format: CCP4 / Size: 15.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.72 Å/pix.
x 160 pix.
= 275.2 Å
1.72 Å/pix.
x 160 pix.
= 275.2 Å
1.72 Å/pix.
x 160 pix.
= 275.2 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.72 Å
Density
Contour LevelBy AUTHOR: 0.0366 / Movie #1: 0.0366
Minimum - Maximum-0.081002615 - 0.15676787
Average (Standard dev.)0.0004241068 (±0.0043063248)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions160160160
Spacing160160160
CellA=B=C: 275.2 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.721.721.72
M x/y/z160160160
origin x/y/z0.0000.0000.000
length x/y/z275.200275.200275.200
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS160160160
D min/max/mean-0.0810.1570.000

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Supplemental data

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Sample components

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Entire SUR1

EntireName: SUR1ABCC8 / Number of components: 2

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Component #1: protein, SUR1

ProteinName: SUR1ABCC8 / Recombinant expression: No
SourceSpecies: Cricetus cricetus (black-bellied hamster)
Source (engineered)Expression System: Rattus norvegicus (Norway rat) / Cell of expression system: INS-1

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Component #2: protein, ATP-binding cassette sub-family C member 8

ProteinName: ATP-binding cassette sub-family C member 8 / Number of Copies: 1 / 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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Experimental details

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Sample preparation

SpecimenSpecimen state: Particle / Method: cryo EM
Sample solutionpH: 7.5
Support filmunspecified
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: C1 (asymmetric) / Number of projections: 499095
3D reconstructionResolution: 4.34 Å / Resolution method: FSC 0.143 CUT-OFF

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Atomic model buiding

Output model

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