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- PDB-6baa: Cryo-EM structure of the pancreatic beta-cell KATP channel bound ... -

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Basic information

Entry
Database: PDB / ID: 6baa
TitleCryo-EM structure of the pancreatic beta-cell KATP channel bound to ATP and glibenclamide
Components
  • ATP-binding cassette sub-family C member 8
  • ATP-sensitive inward rectifier potassium channel 11
KeywordsMETAL TRANSPORT / KATP / SUR1 / Kir6.2 / sulfonylurea receptor
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 / ankyrin binding / 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 / ankyrin binding / nervous system process / potassium ion import across plasma membrane / response to ATP / axolemma / potassium channel activity / intercalated disc / response to testosterone / potassium ion transmembrane transport / ATPase-coupled transmembrane transporter activity / voltage-gated potassium channel activity / regulation of ion transmembrane transport / negative regulation of insulin secretion / regulation of insulin secretion / regulation of membrane potential / heat shock protein binding / T-tubule / acrosomal vesicle / response to ischemia / 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 / response to estradiol / ion channel binding / protein C-terminus binding / endosome / ATPase activity / intracellular membrane-bounded organelle / neuronal cell body / response to drug / endoplasmic reticulum / mitochondrion / integral component of membrane / ATP binding / plasma membrane / cytosol
Potassium channel, inwardly rectifying, Kir / Inward rectifier potassium channel transmembrane domain / ABC transporter type 1, transmembrane domain / ABC transporter, conserved site / AAA+ ATPase domain / P-loop containing nucleoside triphosphate hydrolase / ABC transporter type 1, transmembrane domain superfamily / Potassium channel, inwardly rectifying, transmembrane domain / Immunoglobulin E-set / Inward rectifier potassium channel, C-terminal ...Potassium channel, inwardly rectifying, Kir / Inward rectifier potassium channel transmembrane domain / ABC transporter type 1, transmembrane domain / ABC transporter, conserved site / AAA+ ATPase domain / P-loop containing nucleoside triphosphate hydrolase / ABC transporter type 1, transmembrane domain superfamily / Potassium channel, inwardly rectifying, transmembrane domain / Immunoglobulin E-set / Inward rectifier potassium channel, C-terminal / Inward rectifier potassium channel C-terminal domain / ABC transporter / ABC transporter transmembrane region / ABC transporter-like / Potassium channel, inwardly rectifying, Kir6.2 / ATP-binding cassette subfamily C member 8 / Sulphonylurea receptor / Potassium channel, inwardly rectifying, Kir, cytoplasmic / G protein-activated inward rectifier potassium channel 1 / Helix Hairpins - #70 / Helix Hairpins / Immunoglobulin-like / Sandwich / Orthogonal Bundle / Mainly Beta / Mainly Alpha
ATP-binding cassette sub-family C member 8 / ATP-sensitive inward rectifier potassium channel 11
Biological speciesRattus norvegicus (Norway rat)
Cricetus cricetus (black-bellied hamster)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.63 Å
AuthorsMartin, G.M. / Yoshioka, C. / Shyng, S.L.
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: 2017
Title: Anti-diabetic drug binding site in a mammalian K channel revealed by Cryo-EM.
Authors: Gregory M Martin / Balamurugan Kandasamy / Frank DiMaio / Craig Yoshioka / Show-Ling Shyng /
Abstract: Sulfonylureas are anti-diabetic medications that act by inhibiting pancreatic K channels composed of SUR1 and Kir6.2. The mechanism by which these drugs interact with and inhibit the channel has been ...Sulfonylureas are anti-diabetic medications that act by inhibiting pancreatic K channels composed of SUR1 and Kir6.2. The mechanism by which these drugs interact with and inhibit the channel has been extensively investigated, yet it remains unclear where the drug binding pocket resides. Here, we present a cryo-EM structure of a hamster SUR1/rat Kir6.2 channel bound to a high-affinity sulfonylurea drug glibenclamide and ATP at 3.63 Å resolution, which reveals unprecedented details of the ATP and glibenclamide binding sites. Importantly, the structure shows for the first time that glibenclamide is lodged in the transmembrane bundle of the SUR1-ABC core connected to the first nucleotide binding domain near the inner leaflet of the lipid bilayer. Mutation of residues predicted to interact with glibenclamide in our model led to reduced sensitivity to glibenclamide. Our structure provides novel mechanistic insights of how sulfonylureas and ATP interact with the K channel complex to inhibit channel activity.
Validation Report
SummaryFull reportAbout validation report
History
DepositionOct 12, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 1, 2017Provider: repository / Type: Initial release
Revision 1.1Feb 28, 2018Group: Database references / Category: citation / Item: _citation.title
Revision 1.2Mar 28, 2018Group: Data collection / Database references / Category: citation / Item: _citation.title
Revision 1.3Dec 25, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization

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Structure visualization

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Assembly

Deposited unit
A: ATP-sensitive inward rectifier potassium channel 11
B: ATP-sensitive inward rectifier potassium channel 11
C: ATP-sensitive inward rectifier potassium channel 11
D: ATP-sensitive inward rectifier potassium channel 11
E: ATP-binding cassette sub-family C member 8
F: ATP-binding cassette sub-family C member 8
G: ATP-binding cassette sub-family C member 8
H: ATP-binding cassette sub-family C member 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)887,92216
Polymers883,9178
Non-polymers4,0058
Water0
1


TypeNameSymmetry operationNumber
identity operation1_5551
Buried area41760 Å2
ΔGint-312 kcal/mol
Surface area299500 Å2

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Components

#1: 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.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Kcnj11 / Cell line (production host): INS-1 / Production host: Rattus norvegicus (Norway rat) / References: UniProt: P70673
#2: Protein
ATP-binding cassette sub-family C member 8 / Sulfonylurea receptor 1


Mass: 177333.578 Da / Num. of mol.: 4
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
#3: Chemical
ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE / Adenosine triphosphate


Mass: 507.181 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Feature type: SUBJECT OF INVESTIGATION / Comment: ATP, energy-carrying molecule*YM
#4: Chemical
ChemComp-GBM / 5-chloro-N-(2-{4-[(cyclohexylcarbamoyl)sulfamoyl]phenyl}ethyl)-2-methoxybenzamide / Glibenclamide, Glyburide / Glibenclamide


Mass: 494.004 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C23H28ClN3O5S / Feature type: SUBJECT OF INVESTIGATION / Comment: medication*YM

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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
1Pancreatic beta-cell ATP-sensitive K+ channel (KATP)COMPLEX#1-#20RECOMBINANT
2ATP-sensitive K+ channel subunit Kir6.2COMPLEX#11RECOMBINANT
3ATP-binding cassette sub-family C member 8COMPLEX#21RECOMBINANT
Molecular weightValue: 0.95 MDa / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
11Rattus norvegicus (Norway rat)10116
21Cricetus cricetus (black-bellied hamster)10034
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
11Rattus norvegicus (Norway rat)10116
21Rattus norvegicus (Norway rat)10116
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
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

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C4 (4 fold cyclic)
3D reconstructionResolution: 3.63 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 59417 / Symmetry type: POINT

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