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- PDB-5j71: Crystal structure of pyruvate dehydrogenase kinase isoform 2 in c... -

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Basic information

Entry
Database: PDB / ID: 5j71
TitleCrystal structure of pyruvate dehydrogenase kinase isoform 2 in complex with inhibitor PS35
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 / regulation of acetyl-CoA biosynthetic process from pyruvate / pyruvate dehydrogenase (acetyl-transferring) kinase activity / 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 / regulation of acetyl-CoA biosynthetic process from pyruvate / pyruvate dehydrogenase (acetyl-transferring) kinase activity / 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 / Histidine kinase/HSP90-like ATPase superfamily / Up-down Bundle / 2-Layer Sandwich / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-P35 / L(+)-TARTARIC ACID / [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.65 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
CitationJournal: 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.
History
DepositionApr 5, 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)45,7733
Polymers45,2331
Non-polymers5402
Water4,288238
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)91,5466
Polymers90,4672
Non-polymers1,0794
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation10_555-x,-y,z1
Buried area4180 Å2
ΔGint-21 kcal/mol
Surface area30250 Å2
MethodPISA
Unit cell
Length a, b, c (Å)110.746, 110.746, 228.584
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number98
Space group name H-MI4122

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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-TLA / L(+)-TARTARIC ACID


Mass: 150.087 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H6O6
#3: Chemical ChemComp-P35 / 4-({5-[(piperidin-4-yl)amino]-1,3-dihydro-2H-isoindol-2-yl}sulfonyl)benzene-1,3-diol


Mass: 389.469 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H23N3O4S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 238 / 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: 3.87 Å3/Da / Density % sol: 68.25 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 4.6
Details: 0.9 M ammonium tartrate, 0.1 M sodium acetate pH 4.6

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jul 18, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.65→50 Å / Num. obs: 85125 / % possible obs: 99.8 % / Redundancy: 11.3 % / Rmerge(I) obs: 0.049 / Rsym value: 0.041 / Net I/σ(I): 47
Reflection shellResolution: 1.65→1.68 Å / Redundancy: 11.4 % / Rmerge(I) obs: 0.949 / Mean I/σ(I) obs: 2.65 / % possible all: 100

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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: 4MPC

4mpc


Resolution: 1.65→33.222 Å / SU ML: 0.15 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 18.64
RfactorNum. reflection% reflection
Rfree0.1971 1999 2.35 %
Rwork0.1837 --
obs0.184 85034 99.72 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.65→33.222 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2736 0 37 239 3012
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.012881
X-RAY DIFFRACTIONf_angle_d1.0573907
X-RAY DIFFRACTIONf_dihedral_angle_d14.011762
X-RAY DIFFRACTIONf_chiral_restr0.059428
X-RAY DIFFRACTIONf_plane_restr0.006495
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.6498-1.6910.24681390.22975769X-RAY DIFFRACTION99
1.691-1.73680.21941410.21015875X-RAY DIFFRACTION100
1.7368-1.78790.24211410.19995893X-RAY DIFFRACTION100
1.7879-1.84560.18811420.18685879X-RAY DIFFRACTION100
1.8456-1.91150.20991410.18045875X-RAY DIFFRACTION100
1.9115-1.9880.19751420.18055891X-RAY DIFFRACTION100
1.988-2.07850.1921420.17825899X-RAY DIFFRACTION100
2.0785-2.18810.18491430.17225914X-RAY DIFFRACTION100
2.1881-2.32510.17891430.16855942X-RAY DIFFRACTION100
2.3251-2.50460.21491420.16985931X-RAY DIFFRACTION100
2.5046-2.75650.20651440.17985980X-RAY DIFFRACTION100
2.7565-3.15510.21991450.18795997X-RAY DIFFRACTION100
3.1551-3.97410.17581450.18256038X-RAY DIFFRACTION100
3.9741-33.22840.18421490.18876152X-RAY DIFFRACTION98
Refinement TLS params.Method: refined / Origin x: 6.9449 Å / Origin y: 17.1033 Å / Origin z: -25.5121 Å
111213212223313233
T0.0604 Å20.0209 Å2-0.0042 Å2-0.0891 Å2-0.0083 Å2--0.0879 Å2
L0.4505 °20.2615 °20.0822 °2-0.3017 °20.2341 °2--0.6285 °2
S-0.0932 Å °-0.0122 Å °0.0949 Å °-0.006 Å °0.0278 Å °0.0203 Å °-0.1152 Å °-0.0211 Å °0.0367 Å °
Refinement TLS groupSelection details: all

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