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- PDB-7y1k: Structure of SUR2A in complex with Mg-ATP, Mg-ADP and repaglinide... -

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Basic information

Entry
Database: PDB / ID: 7y1k
TitleStructure of SUR2A in complex with Mg-ATP, Mg-ADP and repaglinide in the inward-facing conformation
ComponentsATP-binding cassette sub-family C member 9
KeywordsMEMBRANE PROTEIN / SUR2A / ABC transporter / repaglinide
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 / ABC-family proteins mediated transport / response to peptide / potassium channel activator activity / 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 / ABC-family proteins mediated transport / response to peptide / potassium channel activator activity / inward rectifying potassium channel / sulfonylurea receptor activity / response to potassium ion / cardiac conduction / response to oxygen levels / response to hydrogen sulfide / cellular respiration / ATPase-coupled monoatomic cation transmembrane transporter activity / cellular response to chemical stress / coronary vasculature development / cardiac muscle cell contraction / regulation of potassium ion transmembrane transport / circulatory system development / cellular response to potassium ion / heterocyclic compound binding / : / syntaxin binding / blood circulation / Ion homeostasis / response to ATP / response to stress / blood vessel development / cellular response to ATP / potassium ion import across plasma membrane / fatty acid oxidation / monoatomic cation transmembrane transport / action potential / ATPase-coupled transmembrane transporter activity / potassium channel activity / potassium channel regulator activity / ABC-type transporter activity / heart morphogenesis / ATP metabolic process / skeletal muscle tissue development / negative regulation of blood pressure / potassium ion transmembrane transport / T-tubule / acrosomal vesicle / cellular response to calcium ion / blood vessel diameter maintenance / sarcomere / response to activity / regulation of membrane potential / mitochondrion organization / response to hydrogen peroxide / sarcolemma / potassium ion transport / regulation of blood pressure / transmembrane transport / response to estrogen / vasodilation / cellular response to xenobiotic stimulus / MAPK cascade / heart development / fibroblast proliferation / defense response to virus / gene expression / transmembrane transporter binding / response to hypoxia / response to xenobiotic stimulus / regulation of transcription by RNA polymerase II / negative regulation of apoptotic process / protein-containing complex binding / 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
ADENOSINE-5'-DIPHOSPHATE / ADENOSINE-5'-TRIPHOSPHATE / Repaglinide / ATP-binding cassette sub-family C member 9
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsChen, L. / Ding, D. / Hou, T.
Funding support China, 3items
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, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 14, 2023Provider: repository / Type: Initial release
Revision 1.1Oct 11, 2023Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: ATP-binding cassette sub-family C member 9
hetero molecules


Theoretical massNumber of molelcules
Total (without water)175,7366
Polymers174,3001
Non-polymers1,4365
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein ATP-binding cassette sub-family C member 9 / Sulfonylurea receptor 2


Mass: 174300.422 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Abcc9, Sur2 / Production host: Homo sapiens (human) / References: UniProt: Q63563
#2: Chemical ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE


Mass: 507.181 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Feature type: SUBJECT OF INVESTIGATION / Comment: ATP, energy-carrying molecule*YM
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-BJX / Repaglinide / 2-ethoxy-4-[2-({(1S)-3-methyl-1-[2-(piperidin-1-yl)phenyl]butyl}amino)-2-oxoethyl]benzoic acid


Mass: 452.586 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H36N2O4
#5: Chemical ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE


Mass: 427.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: ADP, energy-carrying molecule*YM
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: ATP-binding cassette sub-family C member 9, isoform A / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 174 kDa/nm / Experimental value: NO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1800 nm
Image recordingElectron dose: 52 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: cryoSPARC / Version: 3.1.0 / Category: 3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 61007 / Symmetry type: POINT

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