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- PDB-5j6a: Crystal structure of pyruvate dehydrogenase kinase isoform 2 in c... -

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Basic information

Entry
Database: PDB / ID: 5j6a
TitleCrystal structure of pyruvate dehydrogenase kinase isoform 2 in complex with inhibitor PS46
Components[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial
KeywordsTransferase/Transferase Inhibitor / GHKL protein kinase / pyruvate dehydrogenase complex / Mitochondrial protein kinases / Impaired glucose oxidation / Hepatic steatosis / Type 2 diabetes / Cancer / Bergerat nucleotide-binding fold / protein kinase / Transferase-Transferase Inhibitor complex
Function / homology
Function and homology information


[pyruvate dehydrogenase (acetyl-transferring)] kinase / pyruvate dehydrogenase (acetyl-transferring) kinase activity / regulation of pyruvate decarboxylation to acetyl-CoA / Regulation of pyruvate dehydrogenase (PDH) complex / regulation of ketone metabolic process / pyruvate dehydrogenase complex / regulation of pH / cellular response to nutrient / Signaling by Retinoic Acid / regulation of gluconeogenesis ...[pyruvate dehydrogenase (acetyl-transferring)] kinase / pyruvate dehydrogenase (acetyl-transferring) kinase activity / regulation of pyruvate decarboxylation to acetyl-CoA / Regulation of pyruvate dehydrogenase (PDH) complex / regulation of ketone metabolic process / pyruvate dehydrogenase complex / regulation of pH / cellular response to nutrient / Signaling by Retinoic Acid / regulation of gluconeogenesis / intrinsic apoptotic signaling pathway by p53 class mediator / regulation of glucose metabolic process / regulation of calcium-mediated signaling / cellular response to reactive oxygen species / glucose metabolic process / insulin receptor signaling pathway / glucose homeostasis / protein kinase activity / mitochondrial matrix / protein homodimerization activity / mitochondrion / nucleoplasm / ATP binding / cytosol
Similarity search - Function
Alpha-ketoacid/pyruvate dehydrogenase kinase, N-terminal domain / Branched-chain alpha-ketoacid dehydrogenase kinase/Pyruvate dehydrogenase kinase, N-terminal / Alpha-ketoacid/pyruvate dehydrogenase kinase, N-terminal domain superfamily / PDK/BCKDK protein kinase / Mitochondrial branched-chain alpha-ketoacid dehydrogenase kinase / Butyryl-CoA Dehydrogenase, subunit A; domain 3 / Histidine kinase domain / Histidine kinase domain profile. / Histidine kinase-like ATPase, C-terminal domain / Heat Shock Protein 90 ...Alpha-ketoacid/pyruvate dehydrogenase kinase, N-terminal domain / Branched-chain alpha-ketoacid dehydrogenase kinase/Pyruvate dehydrogenase kinase, N-terminal / Alpha-ketoacid/pyruvate dehydrogenase kinase, N-terminal domain superfamily / PDK/BCKDK protein kinase / Mitochondrial branched-chain alpha-ketoacid dehydrogenase kinase / Butyryl-CoA Dehydrogenase, subunit A; domain 3 / Histidine kinase domain / Histidine kinase domain profile. / Histidine kinase-like ATPase, C-terminal domain / Heat Shock Protein 90 / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / Histidine kinase-like ATPases / Histidine kinase/HSP90-like ATPase superfamily / Up-down Bundle / 2-Layer Sandwich / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-P46 / [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.045 Å
AuthorsGui, W.J. / Tso, S.C. / Chuang, J.L. / Wu, C.Y. / Qi, X. / Wynn, R.M. / Chuang, D.T.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)DK-62306 United States
Welch FoundationI-1286 United States
Citation
Journal: J. Med. Chem. / Year: 2017
Title: Development of Dihydroxyphenyl Sulfonylisoindoline Derivatives as Liver-Targeting Pyruvate Dehydrogenase Kinase Inhibitors.
Authors: Tso, S.C. / Lou, M. / Wu, C.Y. / Gui, W.J. / Chuang, J.L. / Morlock, L.K. / Williams, N.S. / Wynn, R.M. / Qi, X. / Chuang, D.T.
#1: Journal: To Be Published
Title: Development of Dihydroxyphenyl Sulfonylisoindoline-based Pyruvate Dehydrogenase Kinase Inhibitor Targeting Liver of Diet-induced Obese Mice
Authors: Tso, S.C. / Qi, X. / Wu, C.Y. / Gui, W.J. / Chuang, J.L. / Morlock, L.K. / Williams, N.S. / Wynn, R.M. / Chuang, D.T.
History
DepositionApr 4, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 25, 2017Provider: repository / Type: Initial release
Revision 1.1Feb 22, 2017Group: Database references
Revision 1.2Sep 20, 2017Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Dec 25, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Sep 27, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,7352
Polymers45,2331
Non-polymers5021
Water1,964109
1
A: [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial
hetero molecules

A: [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)91,4704
Polymers90,4672
Non-polymers1,0032
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_455-x-1,-y,z1
Buried area2270 Å2
ΔGint-15 kcal/mol
Surface area30240 Å2
MethodPISA
Unit cell
Length a, b, c (Å)109.389, 109.389, 84.420
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number172
Space group name H-MP64

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Components

#1: Protein [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial / Pyruvate dehydrogenase kinase isoform 2 / PDKII


Mass: 45233.402 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDK2, PDHK2 / Production host: Escherichia coli (E. coli)
References: UniProt: Q15119, [pyruvate dehydrogenase (acetyl-transferring)] kinase
#2: Chemical ChemComp-P46 / (3S)-3-amino-4-[4-({2-[(2,4-dihydroxyphenyl)sulfonyl]-2H-isoindol-5-yl}amino)piperidin-1-yl]-4-oxobutanamide


Mass: 501.555 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H27N5O6S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 109 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 3.22 Å3/Da / Density % sol: 61.84 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.6
Details: 100 mM sodium acetate pH 5.6 9% Isopropanol 100 mM megnesium chloride 50 mM Ammonium Sulfate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.97918 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Mar 18, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.045→50 Å / Num. obs: 36197 / % possible obs: 99.5 % / Redundancy: 7.3 % / CC1/2: 0.741 / Rmerge(I) obs: 0.068 / Net I/σ(I): 24.7
Reflection shellResolution: 2.05→2.09 Å / Redundancy: 7.1 % / Mean I/σ(I) obs: 2.23 / % possible all: 99.2

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Processing

Software
NameVersionClassification
PHENIX(1.10.1_2155: ???)refinement
HKL-3000data reduction
HKL-3000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4MPN

4mpn


Resolution: 2.045→31.513 Å / SU ML: 0.22 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 24.58 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2291 3308 5.52 %
Rwork0.1956 --
obs0.1975 34146 83.88 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.045→31.513 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2704 0 35 109 2848
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082867
X-RAY DIFFRACTIONf_angle_d0.8973895
X-RAY DIFFRACTIONf_dihedral_angle_d13.8641751
X-RAY DIFFRACTIONf_chiral_restr0.053429
X-RAY DIFFRACTIONf_plane_restr0.006497
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.0453-2.07450.2949800.26541371X-RAY DIFFRACTION48
2.0745-2.10550.2952820.26461405X-RAY DIFFRACTION50
2.1055-2.13830.314850.24071449X-RAY DIFFRACTION52
2.1383-2.17340.3089870.22641456X-RAY DIFFRACTION52
2.1734-2.21090.2618920.24431537X-RAY DIFFRACTION54
2.2109-2.25110.24961030.23411605X-RAY DIFFRACTION58
2.2511-2.29430.27091020.21521818X-RAY DIFFRACTION64
2.2943-2.34120.26751200.19112079X-RAY DIFFRACTION73
2.3412-2.3920.22311400.21672434X-RAY DIFFRACTION87
2.392-2.44770.23871550.21252681X-RAY DIFFRACTION97
2.4477-2.50890.24051620.21012770X-RAY DIFFRACTION98
2.5089-2.57670.23621550.21162748X-RAY DIFFRACTION98
2.5767-2.65240.26351610.21862785X-RAY DIFFRACTION98
2.6524-2.7380.23731660.21682726X-RAY DIFFRACTION98
2.738-2.83580.25311600.21052777X-RAY DIFFRACTION99
2.8358-2.94930.27011710.21272777X-RAY DIFFRACTION99
2.9493-3.08340.27361590.2232761X-RAY DIFFRACTION99
3.0834-3.24580.25751630.21322784X-RAY DIFFRACTION99
3.2458-3.44890.25061630.20012779X-RAY DIFFRACTION99
3.4489-3.71480.23561620.17852788X-RAY DIFFRACTION99
3.7148-4.0880.17271640.16582774X-RAY DIFFRACTION99
4.088-4.67780.17921590.14682794X-RAY DIFFRACTION99
4.6778-5.88730.17391530.1732804X-RAY DIFFRACTION99
5.8873-31.51680.21391640.18812704X-RAY DIFFRACTION96

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