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- PDB-6pz9: Cryo-EM structure of the pancreatic beta-cell SUR1 bound to ATP a... -

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Basic information

Entry
Database: PDB / ID: 6pz9
TitleCryo-EM structure of the pancreatic beta-cell SUR1 bound to ATP and repaglinide
Components
  • ATP-binding cassette sub-family C member 8
  • ATP-sensitive inward rectifier potassium channel 11
KeywordsMEMBRANE PROTEIN / KATP / SUR1 / RPG
Function / homology
Function and homology information


inward rectifying potassium channel / ATP-activated inward rectifier potassium channel activity / sulfonylurea receptor activity / cell body fiber / inorganic cation transmembrane transport / ATPase-coupled cation transmembrane transporter activity / inward rectifier potassium channel activity / positive regulation of cation channel activity / potassium ion import across plasma membrane / nervous system process ...inward rectifying potassium channel / ATP-activated inward rectifier potassium channel activity / sulfonylurea receptor activity / cell body fiber / inorganic cation transmembrane transport / ATPase-coupled cation transmembrane transporter activity / inward rectifier potassium channel activity / positive regulation of cation channel activity / potassium ion import across plasma membrane / nervous system process / ankyrin binding / response to ATP / axolemma / intercalated disc / potassium channel activity / potassium ion transmembrane transport / response to testosterone / voltage-gated potassium channel activity / ATPase-coupled transmembrane transporter activity / regulation of ion transmembrane transport / negative regulation of insulin secretion / regulation of insulin secretion / acrosomal vesicle / T-tubule / response to ischemia / heat shock protein binding / regulation of membrane potential / potassium ion transport / cellular response to glucose stimulus / sarcolemma / positive regulation of protein localization to plasma membrane / nuclear envelope / cellular response to nicotine / glucose metabolic process / cellular response to tumor necrosis factor / myelin sheath / ion channel binding / response to estradiol / response to drug / protein C-terminus binding / endosome / ATPase activity / intracellular membrane-bounded organelle / neuronal cell body / endoplasmic reticulum / mitochondrion / integral component of membrane / ATP binding / plasma membrane / cytosol
Inward rectifier potassium channel C-terminal domain / ABC transporter, conserved site / Sulphonylurea receptor / ATP-binding cassette subfamily C member 8 / Potassium channel, inwardly rectifying, Kir6.2 / ABC transporter-like / AAA+ ATPase domain / Potassium channel, inwardly rectifying, Kir, cytoplasmic / Immunoglobulin E-set / Potassium channel, inwardly rectifying, Kir ...Inward rectifier potassium channel C-terminal domain / ABC transporter, conserved site / Sulphonylurea receptor / ATP-binding cassette subfamily C member 8 / Potassium channel, inwardly rectifying, Kir6.2 / ABC transporter-like / AAA+ ATPase domain / Potassium channel, inwardly rectifying, Kir, cytoplasmic / Immunoglobulin E-set / Potassium channel, inwardly rectifying, Kir / ABC transporter type 1, transmembrane domain / P-loop containing nucleoside triphosphate hydrolase / ABC transporter / ABC transporter type 1, transmembrane domain superfamily / ABC transporter transmembrane region / Inward rectifier potassium channel transmembrane domain / Potassium channel, inwardly rectifying, transmembrane domain / Inward rectifier potassium channel, C-terminal
ATP-sensitive inward rectifier potassium channel 11 / ATP-binding cassette sub-family C member 8
Biological speciesCricetus cricetus (black-bellied hamster)
Rattus norvegicus (Norway rat)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.65 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 (NIH/NIDDK) 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 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
SummaryFull reportAbout validation report
History
DepositionJul 31, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 14, 2019Provider: repository / Type: Initial release
Revision 1.1Dec 25, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization

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Assembly

Deposited unit
C: ATP-binding cassette sub-family C member 8
D: ATP-sensitive inward rectifier potassium channel 11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)221,9394
Polymers220,9792
Non-polymers9602
Water0
1


TypeNameSymmetry operationNumber
identity operation1_5551
Buried area2560 Å2
ΔGint-15 kcal/mol
Surface area57100 Å2

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Components

#1: Protein 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: Protein ATP-sensitive inward rectifier potassium channel 11 / BIR / Inward rectifier K(+) channel Kir6.2 / Potassium channel / inwardly rectifying subfamily J member 11


Mass: 43645.719 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Kcnj11 / Cell line (production host): INS - 1 cells clone 832/13 / Production host: Rattus norvegicus (Norway rat) / References: UniProt: P70673
#3: Chemical ChemComp-BJX / Repaglinide / 2-ethoxy-4-[2-({(1S)-3-methyl-1-[2-(piperidin-1-yl)phenyl]butyl}amino)-2-oxoethyl]benzoic acid / Repaglinide


Mass: 452.586 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H36N2O4 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication*YM
#4: Chemical ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE / Adenosine triphosphate


Mass: 507.181 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / 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

Component
IDNameTypeEntity IDParent-IDSource
1KATP-RPG-ATPCOMPLEX1, 20MULTIPLE SOURCES
2SUR1ABCC8COMPLEX11RECOMBINANT
3KATPATP-sensitive potassium channelCOMPLEX21RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Cricetus cricetus (black-bellied hamster)10034
33Rattus norvegicus (Norway rat)10116
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-IDCell
22Rattus norvegicus (Norway rat)10116
33Rattus norvegicus (Norway rat)10116INS - 1 cells clone 832/13
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD
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: FEI FALCON III (4k x 4k)

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Processing

EM software
IDNameCategory
7Cootmodel fitting
13PHENIXmodel refinement
CTF correctionType: NONE
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.65 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 312000 / Symmetry type: POINT
Atomic model buildingPDB-ID: 6BAA

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