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- EMDB-46820: Cryo-EM structure of a SUR1/Kir6.2 ATP-sensitive potassium channe... -

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Entry
Database: EMDB / ID: EMD-46820
TitleCryo-EM structure of a SUR1/Kir6.2 ATP-sensitive potassium channel in the presence of Aekatperone in the closed conformation
Map data
Sample
  • Complex: Kir6.2/SUR1 closed channel in complex with Aekatperone
    • Protein or peptide: ATP-sensitive inward rectifier potassium channel 11
    • Protein or peptide: SUR1
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: POTASSIUM ION
  • Ligand: N-[3-(cyclohexylmethyl)-1H-pyrazol-5-yl]-2-[(1H-imidazol-1-yl)methyl]benzene-1-sulfonamide
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsATP-sensitive potassium channel / KATP channel / SUR1 / Kir6.2 / potassium transport / metabolic sensor / congenital hyperinsulinism / trafficking / pharmacochaperone / TRANSPORT PROTEIN
Function / homology
Function and homology information


Regulation of insulin secretion / ATP sensitive Potassium channels / ABC-family proteins mediated transport / response to resveratrol / ATP-activated inward rectifier potassium channel activity / 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 / response to resveratrol / ATP-activated inward rectifier potassium channel activity / 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 / inward rectifier potassium channel activity / ATPase-coupled monoatomic cation transmembrane transporter activity / regulation of monoatomic ion transmembrane transport / nervous system process / inorganic cation transmembrane transport / ankyrin binding / Ion homeostasis / response to ATP / response to stress / potassium ion import across plasma membrane / response to testosterone / action potential / voltage-gated potassium channel activity / axolemma / intercalated disc / ABC-type transporter activity / cellular response to nutrient levels / negative regulation of insulin secretion / heat shock protein binding / potassium ion transmembrane transport / T-tubule / regulation of insulin secretion / acrosomal vesicle / response to ischemia / regulation of membrane potential / determination of adult lifespan / positive regulation of protein localization to plasma membrane / cellular response to glucose stimulus / potassium ion transport / sarcolemma / cellular response to nicotine / glucose metabolic process / nuclear envelope / cellular response to tumor necrosis factor / 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
SUR1 / ATP-sensitive inward rectifier potassium channel 11
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat) / Mesocricetus auratus (golden hamster)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.1 Å
AuthorsDriggers CM / ElSheikh A / Shyng S-L
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)DK066485 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM129547 United States
Citation
Journal: Elife / Year: 2025
Title: AI-based discovery and cryoEM structural elucidation of a K channel pharmacochaperone.
Authors: Assmaa Elsheikh / Camden M Driggers / Ha H Truong / Zhongying Yang / John Allen / Niel M Henriksen / Katarzyna Walczewska-Szewc / Show-Ling Shyng /
Abstract: Pancreatic K channel trafficking defects underlie congenital hyperinsulinism (CHI) cases unresponsive to the K channel opener diazoxide, the mainstay medical therapy for CHI. Current clinically used ...Pancreatic K channel trafficking defects underlie congenital hyperinsulinism (CHI) cases unresponsive to the K channel opener diazoxide, the mainstay medical therapy for CHI. Current clinically used K channel inhibitors have been shown to act as pharmacochaperones and restore surface expression of trafficking mutants; however, their therapeutic utility for K trafficking-impaired CHI is hindered by high affinity binding, which limits functional recovery of rescued channels. Recent structural studies of K channels employing cryo-electron microscopy (cryoEM) have revealed a promiscuous pocket where several known K pharmacochaperones bind. The structural knowledge provides a framework for discovering K channel pharmacochaperones with desired reversible inhibitory effects to permit functional recovery of rescued channels. Using an AI-based virtual screening technology AtomNet followed by functional validation, we identified a novel compound, termed Aekatperone, which exhibits chaperoning effects on K channel trafficking mutations. Aekatperone reversibly inhibits K channel activity with a half-maximal inhibitory concentration (IC) ~9 μM. Mutant channels rescued to the cell surface by Aekatperone showed functional recovery upon washout of the compound. CryoEM structure of K bound to Aekatperone revealed distinct binding features compared to known high affinity inhibitor pharmacochaperones. Our findings unveil a K pharmacochaperone enabling functional recovery of rescued channels as a promising therapeutic for CHI caused by K trafficking defects.
#1: Journal: Elife / Year: 2024
Title: AI-Based Discovery and CryoEM Structural Elucidation of a KATP Channel Pharmacochaperone
Authors: ElSheikh A / Driggers CM / Truong HH / Yang Z / Allen J / Henriksen N / Walczewska-Szewc K / Shyng SL
History
DepositionAug 30, 2024-
Header (metadata) releaseFeb 12, 2025-
Map releaseFeb 12, 2025-
UpdateApr 9, 2025-
Current statusApr 9, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_46820.png

Downloads & links

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Map

FileDownload / File: emd_46820.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
1.05 Å/pix.
x 512 pix.
= 538.368 Å		1.05 Å/pix.
x 512 pix.
= 538.368 Å		1.05 Å/pix.
x 512 pix.
= 538.368 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.0515 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.08
Minimum - Maximum-0.1778364 - 0.41166604
Average (Standard dev.)0.00029232126 (±0.012466612)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 538.368 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_46820_msk_1.map
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Half map: #2

Fileemd_46820_half_map_1.map
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Half map: #1

Fileemd_46820_half_map_2.map
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Sample components

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Entire : Kir6.2/SUR1 closed channel in complex with Aekatperone

EntireName: Kir6.2/SUR1 closed channel in complex with Aekatperone
Components
  • Complex: Kir6.2/SUR1 closed channel in complex with Aekatperone
    • Protein or peptide: ATP-sensitive inward rectifier potassium channel 11
    • Protein or peptide: SUR1
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: POTASSIUM ION
  • Ligand: N-[3-(cyclohexylmethyl)-1H-pyrazol-5-yl]-2-[(1H-imidazol-1-yl)methyl]benzene-1-sulfonamide
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Kir6.2/SUR1 closed channel in complex with Aekatperone

SupramoleculeName: Kir6.2/SUR1 closed channel in complex with Aekatperone
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Details: Kir6.2/SUR1 KATP channel in the closed conformation in complex with ATP and Aekatperone
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 880 KDa

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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 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 43.661762 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 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: SUR1

MacromoleculeName: SUR1 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mesocricetus auratus (golden hamster) / Organ: pancreas / Cell: Beta Cell
Molecular weightTheoretical: 177.296578 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 RAIGKLPIAM RALTNYQRLC VAFDAQARKD TQSPQGARAI WRALCHAFGR RLILSSTFRI LADLLGFAGP LCI FGIVDH LGKENHVFQP KTQFLGVYFV SSQEFLGNAY VLAVLLFLAL LLQRTFLQAS YYVAIETGIN LRGAIQTKIY NKIM HLSTS NLSMGEMTAG QICNLVAIDT NQLMWFFFLC PNLWAMPVQI IVGVILLYYI LGVSALIGAA VIILLAPVQY FVATK LSQA QRSTLEHSNE RLKQTNEMLR GMKLLKLYAW ESIFCSRVEV TRRKEMTSLR AFAVYTSISI FMNTAIPIAA VLITFV GHV SFFKESDLSP SVAFASLSLF HILVTPLFLL SSVVRSTVKA LVSVKKLSEF 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 LSHFA ETVEGLTTIR AFRYEARFQQ KLLEYTDSNN IASLFLTAAN RWLEVRMEYI GACVVLIAAA TSISNSLHRE LSAGL VGLG LTYALMVSNY LNWMVRNLAD MEIQLGAVKR IHALLKTEAE SYEGLLAPSL IPKNWPDQGK IQIQNLSVRY DSSLKP VLK HVNALISPGQ KIGICGRTGS GKSSFSLAFF RMVDMFEGRI IIDGIDIAKL PLHTLRSRLS IILQDPVLFS GTIRFNL DP EKKCSDSTLW EALEIAQLKL VVKALPGGLD AIITEGGENF SQGQRQLFCL ARAFVRKTSI FIMDEATASI DMATENIL Q KVVMTAFADR TVVTIAHRVH TILSADLVMV LKRGAILEFD KPETLLSQKD SVFASFVRAD K

UniProtKB: SUR1

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Macromolecule #3: ADENOSINE-5'-TRIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 3 / Number of copies: 5 / Formula: ATP
Molecular weightTheoretical: 507.181 Da
Chemical component information

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

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Macromolecule #4: POTASSIUM ION

MacromoleculeName: POTASSIUM ION / type: ligand / ID: 4 / Number of copies: 6 / Formula: K
Molecular weightTheoretical: 39.098 Da

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Macromolecule #5: N-[3-(cyclohexylmethyl)-1H-pyrazol-5-yl]-2-[(1H-imidazol-1-yl)met...

MacromoleculeName: N-[3-(cyclohexylmethyl)-1H-pyrazol-5-yl]-2-[(1H-imidazol-1-yl)methyl]benzene-1-sulfonamide
type: ligand / ID: 5 / Number of copies: 1 / Formula: A1A4F
Molecular weightTheoretical: 399.51 Da

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Macromolecule #6: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 6 / Number of copies: 1 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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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

Concentration0.15 mg/mL
BufferpH: 7.4
Component:
ConcentrationFormulaName
200.0 mMNaClsodium chloride
100.0 mMKClpotassium chloride
50.0 mMHEPES pH 7.5
1.0 mMATP
0.05 %GDN
0.05 mMAekatperone

Details: MSB with GDN, ATP and AKP
GridModel: EMS Lacey Carbon / Support film - Material: CARBON / Support film - topology: LACEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 60 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 279 K / Instrument: FEI VITROBOT MARK III
DetailsThree microliters of purified Kir6.2-Q52R/FLAG-SUR1 were loaded onto Quantifoil R 1.2/1.3 Au 300 grids prepared with a fresh graphene oxide surface.

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Electron microscopy

MicroscopeTFS KRIOS
DetailsTitan Krios with Falcon K3 at the Pacific Northwest National Lab
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 2 / Number real images: 21012 / Average exposure time: 3.2 sec. / Average electron dose: 55.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 81000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 78490
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7tys

Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.1 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.2.1) / Number images used: 78490
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.2.1)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.2.1)
Final 3D classificationNumber classes: 1 / Software - Name: cryoSPARC (ver. 4.2.1)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

7tys


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementProtocol: FLEXIBLE FIT
Output model

PDB-9dfx:
Cryo-EM structure of a SUR1/Kir6.2 ATP-sensitive potassium channel in the presence of Aekatperone in the closed conformation

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