6PZC

Cryo-EM structure of the pancreatic beta-cell SUR1 bound to carbamazepine


Experimental Data Snapshot

  • Method: ELECTRON MICROSCOPY
  • Resolution: 4.34 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

wwPDB Validation 3D Report Full Report


This is version 1.0 of the entry. See complete history

Literature

Mechanism of pharmacochaperoning in a mammalian KATPchannel revealed by cryo-EM.

Martin, G.M.Sung, M.W.Yang, Z.Innes, L.M.Kandasamy, B.David, L.L.Yoshioka, C.Shyng, S.L.

(2019) Elife 8: --

  • DOI: 10.7554/eLife.46417
  • Primary Citation of Related Structures:  

  • PubMed Abstract: 
  • ATP-sensitive potassium (K <sub>ATP </sub>) 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. ...

    ATP-sensitive potassium (K ATP ) 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 ATP 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 ATP 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.


    Organizational Affiliation

    Department of Biomedical Engineering, Oregon Health and Science University, Portland, United States.,Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, United States.




Macromolecules

Find similar proteins by: Sequence  |  Structure

Entity ID: 1
MoleculeChainsSequence LengthOrganismDetails
ATP-binding cassette sub-family C member 8
H
1582Cricetus cricetusMutation(s): 0 
Gene Names: ABCC8 (SUR)
Find proteins for Q09427 (Cricetus cricetus)
Go to Gene View: ABCC8
Go to UniProtKB:  Q09427
Experimental Data & Validation

Experimental Data

  • Method: ELECTRON MICROSCOPY
  • Resolution: 4.34 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

Structure Validation

View Full Validation Report or Ramachandran Plots



Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney DiseaseUnited States--

Revision History 

  • Version 1.0: 2019-08-14
    Type: Initial release