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Basic information

Entry
Database: PDB / ID: 5m4m
TitleApplication of Off-Rate Screening in the Identification of Novel Pan-Isoform Inhibitors of Pyruvate Dehydrogenase Kinase
Components[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial
KeywordsTRANSFERASE / Off-Rate Screening / PDHK / HSP90 / SPR / kinase inhibitors / fragment screening / cancer / PDK1 / PDK2 / PDK3 / PDK4
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-7FW / Chem-TF3 / [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsBaker, L.M. / Brough, P. / Surgenor, A.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Application of Off-Rate Screening in the Identification of Novel Pan-Isoform Inhibitors of Pyruvate Dehydrogenase Kinase.
Authors: Brough, P.A. / Baker, L. / Bedford, S. / Brown, K. / Chavda, S. / Chell, V. / D'Alessandro, J. / Davies, N.G. / Davis, B. / Le Strat, L. / Macias, A.T. / Maddox, D. / Mahon, P.C. / Massey, A. ...Authors: Brough, P.A. / Baker, L. / Bedford, S. / Brown, K. / Chavda, S. / Chell, V. / D'Alessandro, J. / Davies, N.G. / Davis, B. / Le Strat, L. / Macias, A.T. / Maddox, D. / Mahon, P.C. / Massey, A.J. / Matassova, N. / McKenna, S. / Meissner, J.W. / Moore, J.D. / Murray, J.B. / Northfield, C.J. / Parry, C. / Parsons, R. / Roughley, S.D. / Shaw, T. / Simmonite, H. / Stokes, S. / Surgenor, A. / Stefaniak, E. / Robertson, A. / Wang, Y. / Webb, P. / Whitehead, N. / Wood, M.
History
DepositionOct 18, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 22, 2017Provider: repository / Type: Initial release
Revision 1.1Apr 5, 2017Group: Database references
Revision 1.2Jan 17, 2024Group: 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)47,2776
Polymers46,2911
Non-polymers9865
Water1,928107
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1170 Å2
ΔGint-32 kcal/mol
Surface area16130 Å2
MethodPISA
Unit cell
Length a, b, c (Å)108.651, 108.651, 83.657
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: 46290.727 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 BL21(DE3) (bacteria)
References: UniProt: Q15119, [pyruvate dehydrogenase (acetyl-transferring)] kinase
#2: Chemical ChemComp-7FW / ~{N}-[4-[methyl(quinoxalin-6-ylmethyl)carbamoyl]phenyl]-2,4-bis(oxidanyl)-~{N}-(phenylmethyl)benzamide


Mass: 518.563 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H26N4O4
#3: Chemical ChemComp-TF3 / N-(2-AMINOETHYL)-2-{3-CHLORO-4-[(4-ISOPROPYLBENZYL)OXY]PHENYL} ACETAMIDE


Mass: 360.878 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H25ClN2O2
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Cl
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 107 / 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: 3.08 Å3/Da / Density % sol: 60.06 %
Crystal growTemperature: 277 K / Method: vapor diffusion / pH: 5.8
Details: 0.1 M SODIUM ACETATE PH 5.8 0.125 M MAGNESIUM CHLORIDE 6% ISOPROPANOL

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RUH3R / Wavelength: 1.5412 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Jun 30, 2010 / Details: OSMIC BLUE MIRRORS
RadiationMonochromator: CU FILTER / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5412 Å / Relative weight: 1
ReflectionResolution: 2.4→29.37 Å / Num. obs: 21000 / % possible obs: 95.3 % / Redundancy: 2.01 % / Rmerge(I) obs: 0.109 / Net I/σ(I): 4.9
Reflection shellResolution: 2.4→2.49 Å / Redundancy: 1.97 % / Rmerge(I) obs: 0.57 / Mean I/σ(I) obs: 1.1 / % possible all: 93.5

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
d*TREKdata reduction
d*TREKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2BU8

2bu8


Resolution: 2.4→27.89 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.931 / SU B: 14.207 / SU ML: 0.276 / Cross valid method: THROUGHOUT / ESU R: 0.322 / ESU R Free: 0.249 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2617 1083 5.2 %RANDOM
Rwork0.21663 ---
obs0.21894 19890 95.1 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 59.832 Å2
Baniso -1Baniso -2Baniso -3
1--0.11 Å2-0.06 Å2-0 Å2
2---0.11 Å20 Å2
3---0.37 Å2
Refinement stepCycle: 1 / Resolution: 2.4→27.89 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2752 0 67 107 2926
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0192885
X-RAY DIFFRACTIONr_bond_other_d0.0020.022728
X-RAY DIFFRACTIONr_angle_refined_deg1.8451.9973905
X-RAY DIFFRACTIONr_angle_other_deg1.1163.0036234
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.655340
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.54424.063128
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.07115489
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.6371515
X-RAY DIFFRACTIONr_chiral_restr0.10.2425
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0213197
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02638
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it4.2425.7591372
X-RAY DIFFRACTIONr_mcbond_other4.2095.7571371
X-RAY DIFFRACTIONr_mcangle_it6.5248.6051708
X-RAY DIFFRACTIONr_mcangle_other6.5248.6081709
X-RAY DIFFRACTIONr_scbond_it4.4156.2491510
X-RAY DIFFRACTIONr_scbond_other4.4176.251509
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other7.0889.1882193
X-RAY DIFFRACTIONr_long_range_B_refined11.10954.39912189
X-RAY DIFFRACTIONr_long_range_B_other11.11454.40912167
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.4→2.462 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.398 83 -
Rwork0.397 1429 -
obs--93.1 %

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