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- PDB-6pzi: Cryo-EM structure of the pancreatic beta-cell SUR1 bound to ATP only -

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Basic information

Entry
Database: PDB / ID: 6pzi
TitleCryo-EM structure of the pancreatic beta-cell SUR1 bound to ATP only
ComponentsATP-binding cassette sub-family C member 8
KeywordsMEMBRANE PROTEIN / KATP / SUR1 / ATP
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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.5 Å
AuthorsShyng, S.L. / Yoshioka, C. / Martin, G.M. / Sung, M.W.
Funding support United States, 1items
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 Report
SummaryFull reportAbout validation report
History
DepositionJul 31, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 14, 2019Provider: repository / Type: Initial release

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Assembly

Deposited unit
G: ATP-binding cassette sub-family C member 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)177,8412
Polymers177,3341
Non-polymers5071
Water0
1


TypeNameSymmetry operationNumber
identity operation1_5551
Buried area550 Å2
ΔGint-4 kcal/mol
Surface area71950 Å2

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Components

#1: Protein/peptide ATP-binding cassette sub-family C member 8 / SUR1 / Sulfonylurea receptor 1


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
#2: Chemical ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE


Mass: 507.181 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Adenosine triphosphate / Comment: ATP (energy-carrying molecule) *YM
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: 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
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: unspecified
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 40 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

EM software
IDNameCategory
7Cootmodel fitting
9PHENIXmodel refinement
CTF correctionType: NONE
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 4.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 123757 / Symmetry type: POINT

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