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- EMDB-20530: Cryo-EM structure of the pancreatic beta-cell SUR1 bound to ATP a... -

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Basic information

Entry
Database: EMDB / ID: EMD-20530
TitleCryo-EM structure of the pancreatic beta-cell SUR1 bound to ATP and glibenclamide
Map dataSUR1-GBC-ATP state
Sample
  • Complex: KATP-RPG-ATP
    • Complex: SUR1ABCC8
      • Protein or peptide: ATP-binding cassette sub-family C member 8
    • Complex: KNtp
      • Protein or peptide: ATP-sensitive inward rectifier potassium channel 11
  • Ligand: 5-chloro-N-(2-{4-[(cyclohexylcarbamoyl)sulfamoyl]phenyl}ethyl)-2-methoxybenzamide
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
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: 3.74 Å
AuthorsShyng SL / Yoshioka C / Martin GM / Sung MW
Funding support United States, 1 items
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.
History
DepositionJul 31, 2019-
Header (metadata) releaseAug 14, 2019-
Map releaseAug 14, 2019-
UpdateOct 7, 2020-
Current statusOct 7, 2020Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.00952
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.00952
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6pza
  • Surface level: 0.00952
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-6pza
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_20530.png

Downloads & links

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Map

FileDownload / File: emd_20530.map.gz / Format: CCP4 / Size: 38.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSUR1-GBC-ATP state
Voxel sizeX=Y=Z: 0.855 Å
Density
Contour LevelBy AUTHOR: 0.00952 / Movie #1: 0.00952
Minimum - Maximum-0.040358968 - 0.06839855
Average (Standard dev.)0.00066252414 (±0.0040555242)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin159180121
Dimensions252152261
Spacing152252261
CellA: 129.96 Å / B: 215.46 Å / C: 223.155 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.8550.8550.855
M x/y/z152252261
origin x/y/z0.0000.0000.000
length x/y/z129.960215.460223.155
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ162182277
MAP C/R/S123
start NC/NR/NS180159121
NC/NR/NS152252261
D min/max/mean-0.0400.0680.001

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Supplemental data

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Sample components

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Entire : KATP-RPG-ATP

EntireName: KATP-RPG-ATP
Components
  • Complex: KATP-RPG-ATP
    • Complex: SUR1ABCC8
      • Protein or peptide: ATP-binding cassette sub-family C member 8
    • Complex: KNtp
      • Protein or peptide: ATP-sensitive inward rectifier potassium channel 11
  • Ligand: 5-chloro-N-(2-{4-[(cyclohexylcarbamoyl)sulfamoyl]phenyl}ethyl)-2-methoxybenzamide
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE

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Supramolecule #1: KATP-RPG-ATP

SupramoleculeName: KATP-RPG-ATP / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2

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Supramolecule #2: SUR1

SupramoleculeName: SUR1 / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Cricetus cricetus (black-bellied hamster)
Recombinant expressionOrganism: Rattus norvegicus (Norway rat) / Recombinant cell: INS - 1 cells clone 832/13

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Supramolecule #3: KNtp

SupramoleculeName: KNtp / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2
Source (natural)Organism: Rattus norvegicus (Norway rat)
Recombinant expressionOrganism: Rattus norvegicus (Norway rat)

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Macromolecule #1: ATP-binding cassette sub-family C member 8

MacromoleculeName: ATP-binding cassette sub-family C member 8 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Cricetus cricetus (black-bellied hamster)
Molecular weightTheoretical: 177.333578 KDa
Recombinant expressionOrganism: Rattus norvegicus (Norway rat)
SequenceString: MPLAFCGTEN HSAAYRVDQG VLNNGCFVDA LNVVPHVFLL FITFPILFIG WGSQSSKVHI HHSTWLHFPG HNLRWILTFI LLFVLVCEI AEGILSDGVT ESRHLHLYMP AGMAFMAAIT SVVYYHNIET SNFPKLLIAL LIYWTLAFIT KTIKFVKFYD H AIGFSQLR ...String:
MPLAFCGTEN HSAAYRVDQG VLNNGCFVDA LNVVPHVFLL FITFPILFIG WGSQSSKVHI HHSTWLHFPG HNLRWILTFI LLFVLVCEI AEGILSDGVT ESRHLHLYMP AGMAFMAAIT SVVYYHNIET SNFPKLLIAL LIYWTLAFIT KTIKFVKFYD H AIGFSQLR FCLTGLLVIL YGMLLLVEVN VIRVRRYIFF KTPREVKPPE DLQDLGVRFL QPFVNLLSKG TYWWMNAFIK TA HKKPIDL RAIAKLPIAM RALTNYQRLC VAFDAQARKD TQSPQGARAI WRALCHAFGR RLILSSTFRI LADLLGFAGP LCI FGIVDH LGKENHVFQP KTQFLGVYFV SSQEFLGNAY VLAVLLFLAL LLQRTFLQAS YYVAIETGIN LRGAIQTKIY NKIM HMSTS NLSMGEMTAG QICNLVAIDT NQLMWFFFLC PNLWTMPVQI IVGVILLYYI LGVSALIGAA VIILLAPVQY FVATK LSQA QRTTLEHSNE RLKQTNEMLR GMKLLKLYAW ESIFCSRVEV TRRKEMTSLR AFAVYTSISI FMNTAIPIAA VLITFV GHV SFFKESDLSP SVAFASLSLF HILVTPLFLL SSVVRSTVKA LVSVQKLSEF LSSAEIREEQ CAPREPAPQG QAGKYQA VP LKVVNRKRPA REEVRDLLGP LQRLAPSMDG DADNFCVQII GGFFTWTPDG IPTLSNITIR IPRGQLTMIV GQVGCGKS S LLLATLGEMQ KVSGAVFWNS NLPDSEGEDP SSPERETAAG SDIRSRGPVA YASQKPWLLN ATVEENITFE SPFNKQRYK MVIEACSLQP DIDILPHGDQ TQIGERGINL SGGQRQRISV ARALYQQTNV VFLDDPFSAL DVHLSDHLMQ AGILELLRDD KRTVVLVTH KLQYLPHADW IIAMKDGTIQ REGTLKDFQR SECQLFEHWK TLMNRQDQEL EKETVMERKA SEPSQGLPRA M SSRDGLLL DEEEEEEEAA ESEEDDNLSS VLHQRAKIPW RACTKYLSSA GILLLSLLVF SQLLKHMVLV AIDYWLAKWT DS ALVLSPA ARNCSLSQEC DLDQSVYAMV FTLLCSLGIV LCLVTSVTVE WTGLKVAKRL HRSLLNRIIL APMRFFETTP LGS ILNRFS SDCNTIDQHI PSTLECLSRS TLLCVSALTV ISYVTPVFLV ALLPLAVVCY FIQKYFRVAS RDLQQLDDTT QLPL VSHFA ETVEGLTTIR AFRYEARFQQ KLLEYTDSNN IASLFLTAAN RWLEVCMEYI GACVVLIAAA TSISNSLHRE LSAGL VGLG LTYALMVSNY LNWMVRNLAD MEIQLGAVKR IHALLKTEAE SYEGLLAPSL IPKNWPDQGK IQIQNLSVRY DSSLKP VLK HVNTLISPGQ KIGICGRTGS GKSSFSLAFF RMVDMFEGRI IIDGIDIAKL PLHTLRSRLS IILQDPVLFS GTIRFNL DP EKKCSDSTLW EALEIAQLKL VVKALPGGLD AIITEGGENF SQGQRQLFCL ARAFVRKTSI FIMDEATASI DMATENIL Q KVVMTAFADR TVVTIAHRVH TILSADLVMV LKRGAILEFD KPETLLSQKD SVFASFVRAD K

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Macromolecule #2: ATP-sensitive inward rectifier potassium channel 11

MacromoleculeName: ATP-sensitive inward rectifier potassium channel 11 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 43.645719 KDa
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 ITPRHGRLCF MLRVGDLRKS MIISATIHMQ VVRKTTSPEG EVVPLHQVDI PM ENGVGGN SIFLVAPLII YHVIDSNSPL YDLAPSDLHH HQDLEIIVIL EGVVETTGIT TQARTSYLAD EILWGQRFVP IVA EEDGRY SVDYSKFGNT VKVPTPLCTA RQLDEDRSLL DALTLASSRG PLRKRSVAVA KAKPKFSISP DSLS

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Macromolecule #3: 5-chloro-N-(2-{4-[(cyclohexylcarbamoyl)sulfamoyl]phenyl}ethyl)-2-...

MacromoleculeName: 5-chloro-N-(2-{4-[(cyclohexylcarbamoyl)sulfamoyl]phenyl}ethyl)-2-methoxybenzamide
type: ligand / ID: 3 / Number of copies: 1 / Formula: GBM
Molecular weightTheoretical: 494.004 Da
Chemical component information

ChemComp-GBM:
5-chloro-N-(2-{4-[(cyclohexylcarbamoyl)sulfamoyl]phenyl}ethyl)-2-methoxybenzamide / medication*YM / Glibenclamide

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Macromolecule #4: ADENOSINE-5'-TRIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 4 / Number of copies: 1 / Formula: ATP
Molecular weightTheoretical: 507.181 Da
Chemical component information

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM / Adenosine triphosphate

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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
GridDetails: unspecified
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
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / 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 reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.74 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 171420

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Atomic model buiding 1

Initial modelPDB ID:

6baa

Output model

PDB-6pza:
Cryo-EM structure of the pancreatic beta-cell SUR1 bound to ATP and glibenclamide

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