6PZI

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


Experimental Data Snapshot

  • Method: ELECTRON MICROSCOPY
  • Resolution: 4.50 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

wwPDB Validation 3D Report Full Report


This is version 1.1 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
  • Structures With Same Primary Citation

  • PubMed Abstract: 
  • 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. ...

    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 Biochemistry and Molecular Biology, Oregon Health & 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
G
1582Cricetus cricetusMutation(s): 0 
Gene Names: ABCC8SUR
Find proteins for Q09427 (Cricetus cricetus)
Go to UniProtKB:  Q09427
Protein Feature View
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChainsName / Formula / InChI Key2D Diagram3D Interactions
ATP
Query on ATP

Download CCD File 
G
ADENOSINE-5'-TRIPHOSPHATE
C10 H16 N5 O13 P3
ZKHQWZAMYRWXGA-KQYNXXCUSA-N
 Ligand Interaction
Experimental Data & Validation

Experimental Data

  • Method: ELECTRON MICROSCOPY
  • Resolution: 4.50 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

Structure Validation

View Full Validation Report



Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)United States--

Revision History 

  • Version 1.0: 2019-08-14
    Type: Initial release
  • Version 1.1: 2019-12-25
    Changes: Author supporting evidence