|Entry||Database: PDB / ID: 6pzb|
|Title||Cryo-EM structure of the pancreatic beta-cell SUR1 Apo state|
|Components||ATP-binding cassette sub-family C member 8|
|Keywords||MEMBRANE PROTEIN / KATP / SUR1 / apo|
|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
ABC transporter transmembrane region / AAA+ ATPase domain / ABC transporter / ABC transporter type 1, transmembrane domain superfamily / P-loop containing nucleoside triphosphate hydrolase / ABC transporter, conserved site / ABC transporter type 1, transmembrane domain / ABC transporter-like / ATP-binding cassette subfamily C member 8 / Sulphonylurea receptor
ATP-binding cassette sub-family C member 8
|Biological species||Cricetus cricetus (black-bellied hamster)|
|Method||ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.55 Å|
|Authors||Shyng, S.L. / Yoshioka, C. / Martin, G.M. / Sung, M.W.|
|Funding support|| United States, 1items |
|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.
SummaryFull reportAbout validation report
|Structure viewer||Molecule: |
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G: ATP-binding cassette sub-family C member 8
|#1: Protein|| |
Mass: 177333.578 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Cricetus cricetus (black-bellied hamster)
Gene: ABCC8, SUR / Production host: Rattus norvegicus (Norway rat) / References: UniProt: Q09427
|Experiment||Method: ELECTRON MICROSCOPY|
|EM experiment||Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction|
|Component||Name: SUR1ABCC8 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT|
|Source (natural)||Organism: Cricetus cricetus (black-bellied hamster)|
|Source (recombinant)||Organism: Rattus norvegicus (Norway rat) / Cell: INS - 1 cells clone 832/13|
|Buffer solution||pH: 7.5|
|Specimen||Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES|
|Specimen support||Details: unspecified|
|Vitrification||Cryogen name: ETHANE|
-Electron microscopy imaging
Model: Titan Krios / Image courtesy: FEI Company
|Microscopy||Model: FEI TITAN KRIOS|
|Electron gun||Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM|
|Electron lens||Mode: BRIGHT FIELDBright-field microscopy|
|Image recording||Electron dose: 40 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)|
|CTF correction||Type: NONE|
|Symmetry||Point symmetry: C1 (asymmetric)|
|3D reconstruction||Resolution: 4.55 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 90058 / Symmetry type: POINT|
|Atomic model building||PDB-ID: 6BAA|
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