|Entry||Database: EMDB / ID: EMD-20533|
|Title||Cryo-EM structure of the pancreatic beta-cell SUR1 Apo state|
|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
ATP-binding cassette subfamily C member 8 / Sulphonylurea receptor / ABC transporter-like / AAA+ ATPase domain / ABC transporter type 1, transmembrane domain / ABC transporter, conserved site / P-loop containing nucleoside triphosphate hydrolase / ABC transporter type 1, transmembrane domain superfamily
ATP-binding cassette sub-family C member 8
|Biological species||Cricetus cricetus (black-bellied hamster)|
|Method||single particle reconstruction / cryo EM / Resolution: 4.55 Å|
|Authors||Shyng SL / Yoshioka C / Martin GM / Sung MW|
|Funding support|| United States, 1 items |
|Citation||Journal: 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 β- ...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 Report||Summary, Full report, XML, About validation report|
|Structure viewer||EM map: |
Downloads & links
|File||Download / File: emd_20533.map.gz / Format: CCP4 / Size: 5.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)|
|Projections & slices|
Images are generated by Spider.
|Voxel size||X=Y=Z: 1.826 Å|
|Symmetry||Space group: 1|
CCP4 map header:
|Entire||Name: SUR1ABCC8 / Number of components: 2|
-Component #1: protein, SUR1
|Protein||Name: SUR1ABCC8 / Recombinant expression: No|
|Source||Species: Cricetus cricetus (black-bellied hamster)|
|Source (engineered)||Expression System: Rattus norvegicus (Norway rat) / Cell of expression system: INS - 1 cells clone 832/13|
-Component #2: protein, ATP-binding cassette sub-family C member 8
|Protein||Name: ATP-binding cassette sub-family C member 8 / Number of Copies: 1 / Recombinant expression: No|
|Mass||Theoretical: 177.333578 kDa|
|Source||Species: Cricetus cricetus (black-bellied hamster)|
|Source (engineered)||Expression System: Rattus norvegicus (Norway rat)|
|Specimen||Specimen state: Particle / Method: cryo EM|
|Sample solution||pH: 7.5|
|Vitrification||Cryogen name: ETHANE|
-Electron microscopy imaging
Model: Titan Krios / Image courtesy: FEI Company
|Imaging||Microscope: FEI TITAN KRIOS|
|Electron gun||Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Electron dose: 40 e/Å2 / Illumination mode: FLOOD BEAM|
|Lens||Imaging mode: BRIGHT FIELD|
|Specimen Holder||Model: OTHER|
|Camera||Detector: GATAN K2 SUMMIT (4k x 4k)|
|Processing||Method: single particle reconstruction / Applied symmetry: C1 (asymmetric) / Number of projections: 90058|
|3D reconstruction||Software: RELION / Resolution: 4.55 Å / Resolution method: FSC 0.143 CUT-OFF|
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