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- EMDB-33564: Structure of SUR2A in complex with Mg-ATP, Mg-ADP and repaglinide... -

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Basic information

Entry
Database: EMDB / ID: EMD-33564
TitleStructure of SUR2A in complex with Mg-ATP, Mg-ADP and repaglinide in the inward-facing conformation
Map dataSharpened map of SUR2A in complex with Mg-ATP, Mg-ADP and RPG.
Sample
  • Complex: ATP-binding cassette sub-family C member 9, isoform A
    • Protein or peptide: ATP-binding cassette sub-family C member 9
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: MAGNESIUM ION
  • Ligand: Repaglinide
  • Ligand: ADENOSINE-5'-DIPHOSPHATE
KeywordsSUR2A / ABC transporter / repaglinide / MEMBRANE PROTEIN
Function / homology
Function and homology information


vascular process in circulatory system / substrate-dependent cell migration, cell contraction / reactive oxygen species biosynthetic process / oxygen metabolic process / ATP sensitive Potassium channels / response to decreased oxygen levels / potassium channel activator activity / ABC-family proteins mediated transport / response to peptide / inward rectifying potassium channel ...vascular process in circulatory system / substrate-dependent cell migration, cell contraction / reactive oxygen species biosynthetic process / oxygen metabolic process / ATP sensitive Potassium channels / response to decreased oxygen levels / potassium channel activator activity / ABC-family proteins mediated transport / response to peptide / inward rectifying potassium channel / sulfonylurea receptor activity / response to potassium ion / circulatory system development / cardiac conduction / response to oxygen levels / cellular response to potassium ion / response to hydrogen sulfide / cellular response to chemical stress / cellular respiration / ATPase-coupled monoatomic cation transmembrane transporter activity / coronary vasculature development / cardiac muscle cell contraction / regulation of potassium ion transmembrane transport / syntaxin binding / inorganic cation transmembrane transport / blood circulation / Ion homeostasis / cellular response to ATP / response to ATP / heterocyclic compound binding / response to stress / blood vessel development / potassium ion import across plasma membrane / monoatomic cation transmembrane transport / fatty acid oxidation / action potential / potassium channel activity / ATPase-coupled transmembrane transporter activity / ABC-type transporter activity / potassium channel regulator activity / ATP metabolic process / heart morphogenesis / skeletal muscle tissue development / negative regulation of blood pressure / potassium ion transmembrane transport / T-tubule / cellular response to calcium ion / acrosomal vesicle / blood vessel diameter maintenance / sarcomere / regulation of membrane potential / response to activity / mitochondrion organization / potassium ion transport / sarcolemma / response to hydrogen peroxide / transmembrane transport / regulation of blood pressure / response to estrogen / vasodilation / MAPK cascade / cellular response to xenobiotic stimulus / heart development / fibroblast proliferation / gene expression / defense response to virus / transmembrane transporter binding / response to hypoxia / response to xenobiotic stimulus / regulation of transcription by RNA polymerase II / protein-containing complex binding / negative regulation of apoptotic process / protein-containing complex / ATP hydrolysis activity / mitochondrion / ATP binding / identical protein binding / membrane / plasma membrane / cytoplasm
Similarity search - Function
ATP-binding cassette subfamily C member 9 / : / Sulphonylurea receptor / : / 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. ...ATP-binding cassette subfamily C member 9 / : / Sulphonylurea receptor / : / 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. / 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 9
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsChen L / Ding D / Hou T
Funding support China, 3 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)91957201 China
National Natural Science Foundation of China (NSFC)31870833 China
National Natural Science Foundation of China (NSFC)31821091 China
CitationJournal: Nat Commun / Year: 2023
Title: The inhibition mechanism of the SUR2A-containing K channel by a regulatory helix.
Authors: Dian Ding / Tianyi Hou / Miao Wei / Jing-Xiang Wu / Lei Chen /
Abstract: K channels are metabolic sensors for intracellular ATP/ADP ratios, play essential roles in many physiological processes, and are implicated in a spectrum of pathological conditions. SUR2A-containing ...K channels are metabolic sensors for intracellular ATP/ADP ratios, play essential roles in many physiological processes, and are implicated in a spectrum of pathological conditions. SUR2A-containing K channels differ from other subtypes in their sensitivity to Mg-ADP activation. However, the underlying structural mechanism remains poorly understood. Here we present a series of cryo-EM structures of SUR2A in the presence of different combinations of Mg-nucleotides and the allosteric inhibitor repaglinide. These structures uncover regulatory helix (R helix) on the NBD1-TMD2 linker, which wedges between NBD1 and NBD2. R helix stabilizes SUR2A in the NBD-separated conformation to inhibit channel activation. The competitive binding of Mg-ADP with Mg-ATP to NBD2 mobilizes the R helix to relieve such inhibition, allowing channel activation. The structures of SUR2B in similar conditions suggest that the C-terminal 42 residues of SUR2B enhance the structural dynamics of NBD2 and facilitate the dissociation of the R helix and the binding of Mg-ADP to NBD2, promoting NBD dimerization and subsequent channel activation.
History
DepositionJun 8, 2022-
Header (metadata) releaseJun 14, 2023-
Map releaseJun 14, 2023-
UpdateOct 11, 2023-
Current statusOct 11, 2023Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_33564.png

Downloads & links

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Map

FileDownload / File: emd_33564.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpened map of SUR2A in complex with Mg-ATP, Mg-ADP and RPG.
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 320 pix.
= 266.88 Å		0.83 Å/pix.
x 320 pix.
= 266.88 Å		0.83 Å/pix.
x 320 pix.
= 266.88 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.834 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.475
Minimum - Maximum-1.4666169 - 2.3452346
Average (Standard dev.)0.0017293192 (±0.06792337)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 266.88 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half-A map of SUR2A in complex with Mg-ATP, Mg-ADP and RPG.

Fileemd_33564_half_map_1.map
AnnotationHalf-A map of SUR2A in complex with Mg-ATP, Mg-ADP and RPG.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half-B map of SUR2A in complex with Mg-ATP, Mg-ADP and RPG.

Fileemd_33564_half_map_2.map
AnnotationHalf-B map of SUR2A in complex with Mg-ATP, Mg-ADP and RPG.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : ATP-binding cassette sub-family C member 9, isoform A

EntireName: ATP-binding cassette sub-family C member 9, isoform A
Components
  • Complex: ATP-binding cassette sub-family C member 9, isoform A
    • Protein or peptide: ATP-binding cassette sub-family C member 9
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: MAGNESIUM ION
  • Ligand: Repaglinide
  • Ligand: ADENOSINE-5'-DIPHOSPHATE

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Supramolecule #1: ATP-binding cassette sub-family C member 9, isoform A

SupramoleculeName: ATP-binding cassette sub-family C member 9, isoform A / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 174 kDa/nm

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Macromolecule #1: ATP-binding cassette sub-family C member 9

MacromoleculeName: ATP-binding cassette sub-family C member 9 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 174.300422 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MSLSFCGNNI SSYNIYHGVL QNPCFVDALN LVPHVFLLFI TFPILFIGWG SQSSKVQIHH NTWLHFPGHN LRWILTFALL FVHVCEIAE GIVSDSQRAS RHLHLFMPAV MGFVATTTSI VYYHNIETSN FPKLLLALFL YWVMAFITKT IKLVKYWQLG W GMSDLRFC ...String:
MSLSFCGNNI SSYNIYHGVL QNPCFVDALN LVPHVFLLFI TFPILFIGWG SQSSKVQIHH NTWLHFPGHN LRWILTFALL FVHVCEIAE GIVSDSQRAS RHLHLFMPAV MGFVATTTSI VYYHNIETSN FPKLLLALFL YWVMAFITKT IKLVKYWQLG W GMSDLRFC ITGVMVILNG LLMAVEINVI RVRRYVFFMN PQKVKPPEDL QDLGVRFLQP FVNLLSKATY WWMNTLIISA HR KPIDLKA IGKLPIAMRA VTNYVCLKEA YEEQKKKAAD HPNRTPSIWL AMYRAFGRPI LLSSTFRYLA DLLGFAGPLC ISG IVQRVN EPKNNTTRFS ETLSSKEFLE NAHVLAVLLF LALILQRTFL QASYYVTIET GINLRGALLA MIYNKILRLS TSNL SMGEM TLGQINNLVA IETNQLMWFL FLCPNLWAMP VQIIMGVILL YNLLGSSALV GAAVIVLLAP IQYFIATKLA EAQKS TLDY STERLKKTNE ILKGIKLLKL YAWEHIFCKS VEETRMKELS SLKTFALYTS LSIFMNAAIP IAAVLATFVT HAYASG NNL KPAEAFASLS LFHILVTPLF LLSTVVRFAV KAIISVQKLN EFLLSDEIGE DSWRTGEGTL PFESCKKHTG VQSKPIN RK QPGRYHLDNY EQARRLRPAE TEDVAIKVTN GYFSWGSGLA TLSNIDIRIP TGQLTMIVGQ VGCGKSSLLL AILGEMQT L EGKVYWNNVN ESEPSFEATR SRSRYSVAYA AQKPWLLNAT VEENITFGSS FNRQRYKAVT DACSLQPDID LLPFGDQTE IGERGINLSG GQRQRICVAR ALYQNTNIVF LDDPFSALDI HLSDHLMQEG ILKFLQDDKR TVVLVTHKLQ YLTHADWIIA MKDGSVLRE GTLKDIQTKD VELYEHWKTL MNRQDQELEK DMEADQTTLE RKTLRRAMYS REAKAQMEDE DEEEEEEEDE D DNMSTVMR LRTKMPWKTC WWYLTSGGFF LLFLMIFSKL LKHSVIVAID YWLATWTSEY SINDPGKADQ TFYVAGFSIL CG AGIFLCL VTSLTVEWMG LTAAKNLHHN LLNKIILGPI RFFDTTPLGL ILNRFSADTN IIDQHIPPTL ESLTRSTLLC LSA IGMISY ATPVFLIALA PLGVAFYFIQ KYFRVASKDL QELDDSTQLP LLCHFSETAE GLTTIRAFRH ETRFKQRMLE LTDT NNIAY LFLSAANRWL EVRTDYLGAC IVLTASIASI SGSSNSGLVG LGLLYALTIT NYLNWVVRNL ADLEVQMGAV KKVNS FLTM ESENYEGTMD PSQVPEHWPQ EGEIKIHDLC VRYENNLKPV LKHVKAYIKP GQKVGICGRT GSGKSSLSLA FFRMVD IFD GKIVIDGIDI SKLPLHTLRS RLSIILQDPI LFSGSIRFNL DPECKCTDDR LWEALEIAQL KNMVKSLPGG LDATVTE GG ENFSVGQRQL FCLARAFVRK SSILIMDEAT ASIDMATENI LQKVVMTAFA DRTVVTIAHR VSSIMDAGLV LVFSEGIL V ECDTGPNLLQ HKNGLFSTLV MTNK

UniProtKB: ATP-binding cassette sub-family C member 9

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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

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Macromolecule #3: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 3 / Number of copies: 2 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Macromolecule #4: Repaglinide

MacromoleculeName: Repaglinide / type: ligand / ID: 4 / Number of copies: 1 / Formula: BJX
Molecular weightTheoretical: 452.586 Da
Chemical component information

ChemComp-BJX:
Repaglinide / medication*YM

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Macromolecule #5: ADENOSINE-5'-DIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-DIPHOSPHATE / type: ligand / ID: 5 / Number of copies: 1 / Formula: ADP
Molecular weightTheoretical: 427.201 Da
Chemical component information

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM

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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 K3 (6k x 4k) / Average electron dose: 52.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 3.1.0) / Number images used: 61007
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER

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