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- PDB-4mp7: Crystal structure of pyruvate dehydrogenase kinase isoform 2 in c... -

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Basic information

Entry
Database: PDB / ID: 4mp7
TitleCrystal structure of pyruvate dehydrogenase kinase isoform 2 in complex with inhibitor PA7
Components[Pyruvate dehydrogenase [lipoamide]] 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 cellular ketone metabolic process / regulation of pH / cellular response to nutrient / Regulation of pyruvate dehydrogenase (PDH) complex / 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 cellular ketone metabolic process / regulation of pH / cellular response to nutrient / Regulation of pyruvate dehydrogenase (PDH) complex / 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 / glucose homeostasis / insulin receptor signaling pathway / mitochondrial matrix / protein kinase activity / phosphorylation / 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-PFT / 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: 1.8 Å
AuthorsGui, W.J. / Tso, S.C. / Chuang, J.L. / Wu, C.Y. / Qi, X. / Tambar, U.K. / Wynn, R.M. / Chuang, D.T.
CitationJournal: J.Biol.Chem. / Year: 2014
Title: Structure-guided Development of Specific Pyruvate Dehydrogenase Kinase Inhibitors Targeting the ATP-binding Pocket.
Authors: Tso, S.C. / Qi, X. / Gui, W.J. / Wu, C.Y. / Chuang, J.L. / Wernstedt-Asterholm, I. / Morlock, L.K. / Owens, K.R. / Scherer, P.E. / Williams, N.S. / Tambar, U.K. / Wynn, R.M. / Chuang, D.T.
History
DepositionSep 12, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 1, 2014Provider: repository / Type: Initial release
Revision 1.1Mar 5, 2014Group: Database references
Revision 1.2Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: [Pyruvate dehydrogenase [lipoamide]] kinase isozyme 2, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,6393
Polymers45,2331
Non-polymers4052
Water3,837213
1
A: [Pyruvate dehydrogenase [lipoamide]] kinase isozyme 2, mitochondrial
hetero molecules

A: [Pyruvate dehydrogenase [lipoamide]] kinase isozyme 2, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)91,2786
Polymers90,4672
Non-polymers8114
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation10_555-x,-y,z1
Buried area4690 Å2
ΔGint-28 kcal/mol
Surface area32350 Å2
MethodPISA
Unit cell
Length a, b, c (Å)110.007, 110.007, 227.744
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 [lipoamide]] kinase isozyme 2, mitochondrial / Pyruvate dehydrogenase kinase isoform 2 / PDH kinase 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) / Strain (production host): BL21
References: UniProt: Q15119, [pyruvate dehydrogenase (acetyl-transferring)] kinase
#2: Chemical ChemComp-PFT / 4-(1,3-dihydro-2H-isoindol-2-ylcarbonyl)benzene-1,3-diol


Mass: 255.269 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H13NO3
#3: Chemical ChemComp-TLA / L(+)-TARTARIC ACID / Tartaric acid


Mass: 150.087 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H6O6
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 213 / 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: 3.81 Å3/Da / Density % sol: 67.7 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 4.6
Details: 0.9 M ammonium tartrate, 0.1 M sodium acetate pH 4.6, VAPOR DIFFUSION, temperature 293K

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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: Mar 13, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.8→50 Å / Num. all: 64835 / Num. obs: 64743 / % possible obs: 99.9 % / Observed criterion σ(I): -3 / Redundancy: 10.3 % / Rmerge(I) obs: 0.067 / Net I/σ(I): 30.9
Reflection shellResolution: 1.8→1.83 Å / Redundancy: 10.3 % / Rmerge(I) obs: 0.911 / Mean I/σ(I) obs: 2.6 / Num. unique all: 3210 / % possible all: 100

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Processing

Software
NameVersionClassification
HKL-3000data collection
PHENIX(phenix.refine: 1.7.1_743)model building
PHENIX(phenix.refine: 1.7.1_743)refinement
HKL-3000data reduction
HKL-3000data scaling
PHENIX1.7.1_743phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.8→33.019 Å / SU ML: 0.46 / σ(F): 1.34 / Phase error: 17.54 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2051 2000 3.09 %
Rwork0.1909 --
obs0.1913 64711 99.8 %
Solvent computationShrinkage radii: 1.06 Å / VDW probe radii: 1.3 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 60.857 Å2 / ksol: 0.4 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1-1.163 Å20 Å2-0 Å2
2--1.163 Å2-0 Å2
3----2.326 Å2
Refinement stepCycle: LAST / Resolution: 1.8→33.019 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2921 0 29 213 3163
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0063074
X-RAY DIFFRACTIONf_angle_d1.0184176
X-RAY DIFFRACTIONf_dihedral_angle_d13.4621166
X-RAY DIFFRACTIONf_chiral_restr0.069456
X-RAY DIFFRACTIONf_plane_restr0.004537
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.7997-1.84470.29781390.27934361X-RAY DIFFRACTION99
1.8447-1.89460.22751420.22934439X-RAY DIFFRACTION100
1.8946-1.95040.19421400.20684406X-RAY DIFFRACTION100
1.9504-2.01330.20061410.18544427X-RAY DIFFRACTION100
2.0133-2.08520.20291430.18274468X-RAY DIFFRACTION100
2.0852-2.16870.2221420.17844441X-RAY DIFFRACTION100
2.1687-2.26740.20241400.18024424X-RAY DIFFRACTION100
2.2674-2.38690.18871440.17744503X-RAY DIFFRACTION100
2.3869-2.53640.20951420.1874459X-RAY DIFFRACTION100
2.5364-2.73220.18221430.19234478X-RAY DIFFRACTION100
2.7322-3.00690.19911440.19364507X-RAY DIFFRACTION100
3.0069-3.44170.20151440.18754525X-RAY DIFFRACTION100
3.4417-4.33460.20061460.17564565X-RAY DIFFRACTION100
4.3346-33.02440.21551500.20394708X-RAY DIFFRACTION99
Refinement TLS params.Method: refined / Origin x: 6.5811 Å / Origin y: 17.1606 Å / Origin z: -25.1894 Å
111213212223313233
T0.0572 Å20.0127 Å20.0054 Å2-0.0993 Å2-0.0054 Å2--0.1061 Å2
L0.8621 °20.2341 °20.3059 °2-0.8102 °20.5916 °2--1.7126 °2
S-0.0959 Å °-0.0584 Å °0.1384 Å °-0.0277 Å °0.0255 Å °0.024 Å °-0.2062 Å °-0.0514 Å °0.0396 Å °
Refinement TLS groupSelection details: all

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