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- EMDB-26308: Cryo-EM structure of the pancreatic ATP-sensitive potassium chann... -

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Basic information

Entry
Database: EMDB / ID: EMD-26308
TitleCryo-EM structure of the pancreatic ATP-sensitive potassium channel bound to ATP and glibenclamide with Kir6.2-CTD in the down conformation
Map data
Sample
  • Complex: KATP-GBC-ATP-CTDdown
    • Complex: Kir6.2
      • Protein or peptide: Kir6.2
    • Complex: SUR1
      • Protein or peptide: ATP-binding cassette sub-family C member 8 (SUR1)
KeywordsKATP channel / SUR1 / Kir6.2 / glibenclamide / GBC / GBM / sulfonylurea receptor / potassium transport / MEMBRANE PROTEIN / metabolic sensor
Function / homology
Function and homology information


Regulation of insulin secretion / ATP sensitive Potassium channels / ABC-family proteins mediated transport / ATP-activated inward rectifier potassium channel activity / response to resveratrol / inward rectifying potassium channel / sulfonylurea receptor activity / ventricular cardiac muscle tissue development / cell body fiber / CAMKK-AMPK signaling cascade ...Regulation of insulin secretion / ATP sensitive Potassium channels / ABC-family proteins mediated transport / ATP-activated inward rectifier potassium channel activity / response to resveratrol / inward rectifying potassium channel / sulfonylurea receptor activity / ventricular cardiac muscle tissue development / cell body fiber / CAMKK-AMPK signaling cascade / voltage-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / regulation of monoatomic ion transmembrane transport / ATPase-coupled monoatomic cation transmembrane transporter activity / inward rectifier potassium channel activity / nervous system process / : / ankyrin binding / Ion homeostasis / response to ATP / response to stress / response to testosterone / potassium ion import across plasma membrane / action potential / intercalated disc / axolemma / voltage-gated potassium channel activity / potassium channel activity / ABC-type transporter activity / cellular response to nutrient levels / heat shock protein binding / potassium ion transmembrane transport / T-tubule / regulation of insulin secretion / acrosomal vesicle / response to ischemia / determination of adult lifespan / regulation of membrane potential / positive regulation of protein localization to plasma membrane / cellular response to glucose stimulus / negative regulation of insulin secretion / sarcolemma / potassium ion transport / cellular response to nicotine / glucose metabolic process / cellular response to tumor necrosis factor / nuclear envelope / response to estradiol / presynaptic membrane / transmembrane transporter binding / response to hypoxia / endosome / response to xenobiotic stimulus / neuronal cell body / apoptotic process / glutamatergic synapse / protein-containing complex / ATP hydrolysis activity / ATP binding / metal ion binding / plasma membrane / cytoplasm
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 / : ...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: 6.8 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 23, 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_26308.png

Downloads & links

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Map

FileDownload / File: emd_26308.map.gz / Format: CCP4 / Size: 4 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesX (Sec.)Y (Row.)Z (Col.)
1.4 Å/pix.
x 122 pix.
= 170.678 Å		1.4 Å/pix.
x 81 pix.
= 113.319 Å		1.4 Å/pix.
x 107 pix.
= 149.693 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

generated in cubic-lattice coordinate

Voxel sizeX=Y=Z: 1.399 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 1.0
Minimum - Maximum-6.105782 - 9.164749
Average (Standard dev.)0.000000000008044 (±1.0)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin754975
Dimensions81107122
Spacing12281107
CellA: 170.67801 Å / B: 113.319 Å / C: 149.69301 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : KATP-GBC-ATP-CTDdown

EntireName: KATP-GBC-ATP-CTDdown
Components
  • Complex: KATP-GBC-ATP-CTDdown
    • Complex: Kir6.2
      • Protein or peptide: Kir6.2
    • Complex: SUR1
      • Protein or peptide: ATP-binding cassette sub-family C member 8 (SUR1)

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Supramolecule #1: KATP-GBC-ATP-CTDdown

SupramoleculeName: KATP-GBC-ATP-CTDdown / 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: Kir6.2

MacromoleculeName: Kir6.2 / type: protein_or_peptide / ID: 1 / Details: Kir6.2 tetramer / Enantiomer: LEVO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Recombinant expressionOrganism: Rattus norvegicus (Norway rat)
SequenceString: MLSRKGIIPE EYVLTRLAED PTEPRYRTRE RRARFVSKKG NCNVAHKNIR EQGRFLQDVF TTLVDLKWP HTLLIFTMSF LCSWLLFAMV WWLIAFAHGD LAPGEGTNVP CVTSIHSFSS A FLFSIEVQ VTIGFGGRMV TEECPLAILI LIVQNIVGLM INAIMLGCIF ...String:
MLSRKGIIPE EYVLTRLAED PTEPRYRTRE RRARFVSKKG NCNVAHKNIR EQGRFLQDVF TTLVDLKWP HTLLIFTMSF LCSWLLFAMV WWLIAFAHGD LAPGEGTNVP CVTSIHSFSS A FLFSIEVQ VTIGFGGRMV TEECPLAILI LIVQNIVGLM INAIMLGCIF MKTAQAHRRA ET LIFSKHA VITLRHGRLC FMLRVGDLRK SMIISATIHM QVVRKTTSPE GEVVPLHQVD IPM ENGVGG NSIFLVAPLI IYHVIDSNSP LYDLAPSDLH HHQDLEIIVI LEGVVETTGI TTQA RTSYL ADEILWGQRF VPIVAEEDGR YSVDYSKFGN TVKVPTPLCT ARQLDEDRSL LDALT LASS RGPLRKRSVA VAKAKPKFSI SPDSLS

UniProtKB: ATP-sensitive inward rectifier potassium channel 11

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Macromolecule #2: ATP-binding cassette sub-family C member 8 (SUR1)

MacromoleculeName: ATP-binding cassette sub-family C member 8 (SUR1) / type: protein_or_peptide / ID: 2 / Details: SUR1 subunit / 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
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.6 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: EMDB MAP
EMDB ID:

7073

Final reconstructionResolution.type: BY AUTHOR / Resolution: 6.8 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 13000
Initial angle assignmentType: COMMON LINE
Final angle assignmentType: ANGULAR RECONSTITUTION

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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-7u6y:
Cryo-EM structure of the pancreatic ATP-sensitive potassium channel in the presence of glibenclamide and ATP with Kir6.2-CTD in the down conformation

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