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- EMDB-32535: Structure of SUR1 in complex with mitiglinide -

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Basic information

Entry
Database: EMDB / ID: EMD-32535
TitleStructure of SUR1 in complex with mitiglinide
Map data
Sample
  • Complex: Sulfonylurea receptor 1
    • Protein or peptide: ATP-sensitive inward rectifier potassium channel 11,ATP-binding cassette sub-family C member 8 isoform X1
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: (2S)-4-[(3aR,7aS)-1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl]-4-oxidanylidene-2-(phenylmethyl)butanoic acid
Function / homology
Function and homology information


ATP sensitive Potassium channels / ATP-activated inward rectifier potassium channel activity / Regulation of insulin secretion / ABC-family proteins mediated transport / Ion homeostasis / inward rectifying potassium channel / sulfonylurea receptor activity / inward rectifier potassium channel activity / nervous system process / regulation of monoatomic ion transmembrane transport ...ATP sensitive Potassium channels / ATP-activated inward rectifier potassium channel activity / Regulation of insulin secretion / ABC-family proteins mediated transport / Ion homeostasis / inward rectifying potassium channel / sulfonylurea receptor activity / inward rectifier potassium channel activity / nervous system process / regulation of monoatomic ion transmembrane transport / ankyrin binding / response to ATP / potassium ion import across plasma membrane / negative regulation of insulin secretion / ABC-type transporter activity / regulation of membrane potential / potassium ion transport / glucose metabolic process / transmembrane transporter binding / membrane => GO:0016020 / response to xenobiotic stimulus / 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-binding cassette sub-family C member 8 isoform X1 / ATP-sensitive inward rectifier potassium channel 11
Similarity search - Component
Biological speciesMesocricetus auratus (golden hamster)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.21 Å
AuthorsChen L / Wang MM
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)91957201 and 31870833 China
CitationJournal: Front Pharmacol / Year: 2022
Title: Structural Insights Into the High Selectivity of the Anti-Diabetic Drug Mitiglinide.
Authors: Mengmeng Wang / Jing-Xiang Wu / Lei Chen /
Abstract: Mitiglinide is a highly selective fast-acting anti-diabetic drug that induces insulin secretion by inhibiting pancreatic K channels. However, how mitiglinide binds K channels remains unknown. Here, ...Mitiglinide is a highly selective fast-acting anti-diabetic drug that induces insulin secretion by inhibiting pancreatic K channels. However, how mitiglinide binds K channels remains unknown. Here, we show the cryo-EM structure of the SUR1 subunit complexed with mitiglinide. The structure reveals that mitiglinide binds inside the common insulin secretagogue-binding site of SUR1, which is surrounded by TM7, TM8, TM16, and TM17. Mitiglinide locks SUR1 in the NBD-separated inward-facing conformation. The detailed structural analysis of the mitiglinide-binding site uncovers the molecular basis of its high selectivity.
History
DepositionJan 4, 2022-
Header (metadata) releaseNov 16, 2022-
Map releaseNov 16, 2022-
UpdateDec 21, 2022-
Current statusDec 21, 2022Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_32535.png

Downloads & links

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Map

FileDownload / File: emd_32535.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.045 Å
Density
Contour LevelBy AUTHOR: 0.7
Minimum - Maximum-2.4431648 - 4.007441
Average (Standard dev.)0.0067843245 (±0.105272636)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 267.52 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_32535_msk_1.map
Projections & Slices
AxesZYX

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Half map: #1

Fileemd_32535_half_map_1.map
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Histogram (log scale)

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Half map: #2

Fileemd_32535_half_map_2.map
Projections & Slices
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Sample components

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Entire : Sulfonylurea receptor 1

EntireName: Sulfonylurea receptor 1
Components
  • Complex: Sulfonylurea receptor 1
    • Protein or peptide: ATP-sensitive inward rectifier potassium channel 11,ATP-binding cassette sub-family C member 8 isoform X1
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: (2S)-4-[(3aR,7aS)-1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl]-4-oxidanylidene-2-(phenylmethyl)butanoic acid

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Supramolecule #1: Sulfonylurea receptor 1

SupramoleculeName: Sulfonylurea receptor 1 / type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Mesocricetus auratus (golden hamster)

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Macromolecule #1: ATP-sensitive inward rectifier potassium channel 11,ATP-binding c...

MacromoleculeName: ATP-sensitive inward rectifier potassium channel 11,ATP-binding cassette sub-family C member 8 isoform X1
type: protein_or_peptide / ID: 1
Details: Fusion protein of potassium channel, linkers and Abcc8
Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mesocricetus auratus (golden hamster)
Molecular weightTheoretical: 159.439844 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: GPLSRKGIIP EEYVLTRLAE DPAEPRYRTR ERRVDGSGSG SGSAAGSGSG SGSGSGAAAE DLQDLGVRFL QPFVNLLSKG TYWWMNAFI KTAHKKPIDL RAIGKLPIAM RALTNYQRLC VAFDAQARKD TQSPQGARAI WRALCHAFGR RLILSSTFRI L ADLLGFAG ...String:
GPLSRKGIIP EEYVLTRLAE DPAEPRYRTR ERRVDGSGSG SGSAAGSGSG SGSGSGAAAE DLQDLGVRFL QPFVNLLSKG TYWWMNAFI KTAHKKPIDL RAIGKLPIAM RALTNYQRLC VAFDAQARKD TQSPQGARAI WRALCHAFGR RLILSSTFRI L ADLLGFAG PLCIFGIVDH LGKENHVFQP KTQFLGVYFV SSQEFLGNAY VLAVLLFLAL LLQRTFLQAS YYVAIETGIN LR GAIQTKI YNKIMHLSTS NLSMGEMTAG QICNLVAIDT NQLMWFFFLC PNLWAMPVQI IVGVILLYYI LGVSALIGAA VII LLAPVQ YFVATKLSQA QRSTLEHSNE RLKQTNEMLR GMKLLKLYAW ESIFCSRVEV TRRKEMTSLR AFAVYTSISI FMNT AIPIA AVLITFVGHV SFFKESDLSP SVAFASLSLF HILVTPLFLL SSVVRSTVKA LVSVQKLSEF LSSAEIREEQ CAPRE PAPQ GQAGKYQAVP LKVVNRKRPA REEVRDLLGP LQRLAPSMDG DADNFCVQII GGFFTWTPDG IPTLSNITIR IPRGQL TMI VGQVGCGKSS LLLATLGEMQ KVSGAVFWNS NLPDSEGEDP SSPERETAAG SDIRSRGPVA YASQKPWLLN ATVEENI TF ESPFNKQRYK MVIEACSLQP DIDILPHGDQ TQIGERGINL SGGQRQRISV ARALYQQTNV VFLDDPFSAL DVHLSDHL M QAGILELLRD DKRTVVLVTH KLQYLPHADW IIAMKDGTIQ REGTLKDFQR SECQLFEHWK TLMNRQDQEL EKETVMERK ASEPSQGLPR AMSSRDGLLL DEEEEEEEAA ESEEDDNLSS VLHQRAKIPW RACTKYLSSA GILLLSLLVF SQLLKHMVLV AIDYWLAKW TDSALVLSPA ARNCSLSQEC DLDQSVYAMV FTLLCSLGIV LCLVTSVTVE WTGLKVAKRL HRSLLNRIIL A PMRFFETT PLGSILNRFS SDCNTIDQHI PSTLECLSRS TLLCVSALTV ISYVTPVFLV ALLPLAVVCY FIQKYFRVAS RD LQQLDDT TQLPLLSHFA ETVEGLTTIR AFRYEARFQQ KLLEYTDSNN IASLFLTAAN RWLEVRMEYI GACVVLIAAA TSI SNSLHR ELSAGLVGLG LTYALMVSNY LNWMVRNLAD MEIQLGAVKR IHALLKTEAE SYEGLLAPSL IPKNWPDQGK IQIQ NLSVR YDSSLKPVLK HVNALISPGQ KIGICGRTGS GKSSFSLAFF RMVDMFEGRI IIDGIDIAKL PLHTLRSRLS IILQD PVLF SGTIRFNLDP EKKCSDSTLW EALEIAQLKL VVKALPGGLD AIITEGGENF SQGQRQLFCL ARAFVRKTSI FIMDEA TAS IDMATENILQ KVVMTAFADR TVVTIAHRVH TILSADLVMV LKRGAILEFD KPETLLSQKD SVFASFVRAD K

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Macromolecule #2: ADENOSINE-5'-TRIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 2 / 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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Macromolecule #3: (2S)-4-[(3aR,7aS)-1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl]-4-oxi...

MacromoleculeName: (2S)-4-[(3aR,7aS)-1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl]-4-oxidanylidene-2-(phenylmethyl)butanoic acid
type: ligand / ID: 3 / Number of copies: 1 / Formula: 9I0
Molecular weightTheoretical: 315.407 Da
Chemical component information

ChemComp-9I0:
(2S)-4-[(3aR,7aS)-1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl]-4-oxidanylidene-2-(phenylmethyl)butanoic acid / Mitiglinide

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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 / Nominal defocus max: 3.0 µm / Nominal defocus min: 1.5 µm
Image recordingFilm or detector model: DIRECT ELECTRON DE-16 (4k x 4k) / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE / Details: cryo-sparc
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.21 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 82717

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