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- EMDB-26312: Cryo-EM structure of the pancreatic ATP-sensitive potassium chann... -

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Basic information

Entry
Database: EMDB / ID: EMD-26312
TitleCryo-EM structure of the pancreatic ATP-sensitive potassium channel bound to ATP with Kir6.2-CTD in the up conformation
Map data
Sample
  • Complex: KATP-ATP-CTDup
    • Complex: Kir6.2
      • Protein or peptide: ATP-sensitive inward rectifier potassium channel 11
    • Complex: SUR1ABCC8
      • Protein or peptide: ATP-binding cassette sub-family C member 8
KeywordsKATP channel / SUR1 / Kir6.2 / ATP / sulfonylurea receptor / potassium transport / MEMBRANE PROTEIN / metabolic sensor / trafficking defects
Function / homology
Function and homology information


Regulation of insulin secretion / ATP sensitive Potassium channels / ABC-family proteins mediated transport / response to resveratrol / ventricular cardiac muscle tissue development / ATP-activated inward rectifier potassium channel activity / cell body fiber / inward rectifying potassium channel / sulfonylurea receptor activity / CAMKK-AMPK signaling cascade ...Regulation of insulin secretion / ATP sensitive Potassium channels / ABC-family proteins mediated transport / response to resveratrol / ventricular cardiac muscle tissue development / ATP-activated inward rectifier potassium channel activity / cell body fiber / inward rectifying potassium channel / sulfonylurea receptor activity / CAMKK-AMPK signaling cascade / voltage-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / inward rectifier potassium channel activity / ATPase-coupled monoatomic cation transmembrane transporter activity / nervous system process / regulation of monoatomic ion transmembrane transport / inorganic cation transmembrane transport / action potential / ankyrin binding / Ion homeostasis / response to ATP / response to testosterone / potassium ion import across plasma membrane / voltage-gated potassium channel activity / potassium channel activity / regulation of insulin secretion / axolemma / intercalated disc / negative regulation of insulin secretion / ABC-type transporter activity / potassium ion transmembrane transport / T-tubule / heat shock protein binding / regulation of membrane potential / acrosomal vesicle / response to ischemia / determination of adult lifespan / cellular response to glucose stimulus / positive regulation of protein localization to plasma membrane / sarcolemma / potassium ion transport / cellular response to nicotine / glucose metabolic process / response to estradiol / presynaptic membrane / nuclear envelope / cellular response to tumor necrosis factor / transmembrane transporter binding / response to hypoxia / endosome / response to xenobiotic stimulus / neuronal cell body / glutamatergic synapse / apoptotic process / ATP hydrolysis activity / ATP binding / plasma membrane
Similarity search - Function
Potassium channel, inwardly rectifying, Kir6.2 / ATP-binding cassette subfamily C member 8 / Sulphonylurea receptor / Potassium channel, inwardly rectifying, transmembrane domain / Inward rectifier potassium channel transmembrane domain / Potassium channel, inwardly rectifying, Kir, cytoplasmic / Potassium channel, inwardly rectifying, Kir / Inward rectifier potassium channel, C-terminal / Inward rectifier potassium channel C-terminal domain / ABC transporter transmembrane region ...Potassium channel, inwardly rectifying, Kir6.2 / ATP-binding cassette subfamily C member 8 / Sulphonylurea receptor / Potassium channel, inwardly rectifying, transmembrane domain / Inward rectifier potassium channel transmembrane domain / Potassium channel, inwardly rectifying, Kir, cytoplasmic / Potassium channel, inwardly rectifying, Kir / Inward rectifier potassium channel, C-terminal / Inward rectifier potassium channel C-terminal domain / ABC transporter transmembrane region / ABC transporter type 1, transmembrane domain / ABC transporter integral membrane type-1 fused domain profile. / ABC transporter type 1, transmembrane domain superfamily / ABC transporter-like, conserved site / ABC transporters family signature. / ABC transporter / ABC transporter-like, ATP-binding domain / ATP-binding cassette, ABC transporter-type domain profile. / Immunoglobulin E-set / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
ATP-sensitive inward rectifier potassium channel 11 / ATP-binding cassette sub-family C member 8
Similarity search - Component
Biological speciesCricetus cricetus (black-bellied hamster) / Rattus norvegicus (Norway rat)
Methodsingle particle reconstruction / cryo EM / Resolution: 5.7 Å
AuthorsShyng SL / Sung MW / Driggers CM
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)R01 DK066485-13 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.
History
DepositionFeb 24, 2022-
Header (metadata) releaseAug 31, 2022-
Map releaseAug 31, 2022-
UpdateJan 17, 2024-
Current statusJan 17, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_26312.png

Downloads & links

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Map

FileDownload / File: emd_26312.map.gz / Format: CCP4 / Size: 2.3 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.71 Å
Density
Contour LevelBy AUTHOR: 2.0
Minimum - Maximum-6.749626 - 9.981942
Average (Standard dev.)-0.000000000033674 (±1.0)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin593761
Dimensions6791101
Spacing1016791
CellA: 172.71 Å / B: 114.57 Å / C: 155.61 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : KATP-ATP-CTDup

EntireName: KATP-ATP-CTDup
Components
  • Complex: KATP-ATP-CTDup
    • Complex: Kir6.2
      • Protein or peptide: ATP-sensitive inward rectifier potassium channel 11
    • Complex: SUR1ABCC8
      • Protein or peptide: ATP-binding cassette sub-family C member 8

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Supramolecule #1: KATP-ATP-CTDup

SupramoleculeName: KATP-ATP-CTDup / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Cricetus cricetus (black-bellied hamster)

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Supramolecule #2: Kir6.2

SupramoleculeName: Kir6.2 / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1 / Details: Adenovirus-based infection of INS-1 cells
Source (natural)Organism: Cricetus cricetus (black-bellied hamster)

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Supramolecule #3: SUR1

SupramoleculeName: SUR1 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2 / Details: Adenovirus-based infection of INS-1 cells
Source (natural)Organism: Rattus norvegicus (Norway rat)

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Macromolecule #1: ATP-sensitive inward rectifier potassium channel 11

MacromoleculeName: ATP-sensitive inward rectifier potassium channel 11 / type: protein_or_peptide / ID: 1 / Details: tetramer / Enantiomer: LEVO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Recombinant expressionOrganism: Rattus norvegicus (Norway rat)
SequenceString: MLSRKGIIPE EYVLTRLAED PTEPRYRTRE RRARFVSKKG NCNVAHKNIR EQGRFLQDVF TTLVDLKWPH TLLIFTMSFL CSWLLFAMV WWLIAFAHGD LAPGEGTNVP CVTSIHSFSS AFLFSIEVQV TIGFGGRMVT EECPLAILIL IVQNIVGLMI N AIMLGCIF ...String:
MLSRKGIIPE EYVLTRLAED PTEPRYRTRE RRARFVSKKG NCNVAHKNIR EQGRFLQDVF TTLVDLKWPH TLLIFTMSFL CSWLLFAMV WWLIAFAHGD LAPGEGTNVP CVTSIHSFSS AFLFSIEVQV TIGFGGRMVT EECPLAILIL IVQNIVGLMI N AIMLGCIF MKTAQAHRRA ETLIFSKHAV ITLRHGRLCF MLRVGDLRKS MIISATIHMQ VVRKTTSPEG EVVPLHQVDI PM ENGVGGN SIFLVAPLII YHVIDSNSPL YDLAPSDLHH HQDLEIIVIL EGVVETTGIT TQARTSYLAD EILWGQRFVP IVA EEDGRY SVDYSKFGNT VKVPTPLCTA RQLDEDRSLL DALTLASSRG PLRKRSVAVA KAKPKFSISP DSLS

UniProtKB: ATP-sensitive inward rectifier potassium channel 11

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Macromolecule #2: ATP-binding cassette sub-family C member 8

MacromoleculeName: ATP-binding cassette sub-family C member 8 / type: protein_or_peptide / ID: 2 / Details: focused on one SUR1 copy / Enantiomer: LEVO
Source (natural)Organism: Cricetus cricetus (black-bellied hamster)
Recombinant expressionOrganism: Rattus norvegicus (Norway rat)
SequenceString: MPLAFCGTEN HSAAYRVDQG VLNNGCFVDA LNVVPHVFLL FITFPILFIG WGSQSSKVHI HHSTWLHFP GHNLRWILTF ILLFVLVCEI AEGILSDGVT ESRHLHLYMP AGMAFMAAIT S VVYYHNIE TSNFPKLLIA LLIYWTLAFI TKTIKFVKFY DHAIGFSQLR ...String:
MPLAFCGTEN HSAAYRVDQG VLNNGCFVDA LNVVPHVFLL FITFPILFIG WGSQSSKVHI HHSTWLHFP GHNLRWILTF ILLFVLVCEI AEGILSDGVT ESRHLHLYMP AGMAFMAAIT S VVYYHNIE TSNFPKLLIA LLIYWTLAFI TKTIKFVKFY DHAIGFSQLR FCLTGLLVIL YG MLLLVEV NVIRVRRYIF FKTPREVKPP EDLQDLGVRF LQPFVNLLSK GTYWWMNAFI KTA HKKPID LRAIAKLPIA MRALTNYQRL CVAFDAQARK DTQSPQGARA IWRALCHAFG RRLI LSSTF RILADLLGFA GPLCIFGIVD HLGKENHVFQ PKTQFLGVYF VSSQEFLGNA YVLAV LLFL ALLLQRTFLQ ASYYVAIETG INLRGAIQTK IYNKIMHMST SNLSMGEMTA GQICNL VAI DTNQLMWFFF LCPNLWTMPV QIIVGVILLY YILGVSALIG AAVIILLAPV QYFVATK LS QAQRTTLEHS NERLKQTNEM LRGMKLLKLY AWESIFCSRV EVTRRKEMTS LRAFAVYT S ISIFMNTAIP IAAVLITFVG HVSFFKESDL SPSVAFASLS LFHILVTPLF LLSSVVRST VKALVSVQKL SEFLSSAEIR EEQCAPREPA PQGQAGKYQA VPLKVVNRKR PAREEVRDLL GPLQRLAPS MDGDADNFCV QIIGGFFTWT PDGIPTLSNI TIRIPRGQLT MIVGQVGCGK S SLLLATLG EMQKVSGAVF WNSNLPDSEG EDPSSPERET AAGSDIRSRG PVAYASQKPW LL NATVEEN ITFESPFNKQ RYKMVIEACS LQPDIDILPH GDQTQIGERG INLSGGQRQR ISV ARALYQ QTNVVFLDDP FSALDVHLSD HLMQAGILEL LRDDKRTVVL VTHKLQYLPH ADWI IAMKD GTIQREGTLK DFQRSECQLF EHWKTLMNRQ DQELEKETVM ERKASEPSQG LPRAM SSRD GLLLDEEEEE EEAAESEEDD NLSSVLHQRA KIPWRACTKY LSSAGILLLS LLVFSQ LLK HMVLVAIDYW LAKWTDSALV LSPAARNCSL SQECDLDQSV YAMVFTLLCS LGIVLCL VT SVTVEWTGLK VAKRLHRSLL NRIILAPMRF FETTPLGSIL NRFSSDCNTI DQHIPSTL E CLSRSTLLCV SALTVISYVT PVFLVALLPL AVVCYFIQKY FRVASRDLQQ LDDTTQLPL VSHFAETVEG LTTIRAFRYE ARFQQKLLEY TDSNNIASLF LTAANRWLEV CMEYIGACVV LIAAATSIS NSLHRELSAG LVGLGLTYAL MVSNYLNWMV RNLADMEIQL GAVKRIHALL K TEAESYEG LLAPSLIPKN WPDQGKIQIQ NLSVRYDSSL KPVLKHVNTL ISPGQKIGIC GR TGSGKSS FSLAFFRMVD MFEGRIIIDG IDIAKLPLHT LRSRLSIILQ DPVLFSGTIR FNL DPEKKC SDSTLWEALE IAQLKLVVKA LPGGLDAIIT EGGENFSQGQ RQLFCLARAF VRKT SIFIM DEATASIDMA TENILQKVVM TAFADRTVVT IAHRVHTILS ADLVMVLKRG AILEF DKPE TLLSQKDSVF ASFVRADK

UniProtKB: ATP-binding cassette sub-family C member 8

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 2.6 µm / Nominal defocus min: 1.0 µm
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 40.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: EMDB MAP
EMDB ID:

7073

Initial angle assignmentType: COMMON LINE
Final angle assignmentType: ANGULAR RECONSTITUTION
Final reconstructionResolution.type: BY AUTHOR / Resolution: 5.7 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 33000

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Atomic model buiding 1

Initial model
PDB IDChain

6baa

chain_id: A, source_name: PDB, initial_model_type: experimental model

6baa

chain_id: B, source_name: PDB, initial_model_type: experimental model

6baa

chain_id: C, source_name: PDB, initial_model_type: experimental model

6baa

chain_id: D, source_name: PDB, initial_model_type: experimental model

6pz9

chain_id: E, source_name: PDB, initial_model_type: experimental model
Output model

PDB-7uaa:
CryoEM structure of the pancreatic ATP-sensitive potassium channel in the ATP-bound state with Kir6.2-CTD in the up conformation

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