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- PDB-5m4p: Application of Off-Rate Screening in the Identification of Novel ... -

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Basic information

Entry
Database: PDB / ID: 5m4p
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-7FE / Chem-TF3 / [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.3 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 1.2Oct 24, 2018Group: Advisory / Data collection / Derived calculations
Category: pdbx_unobs_or_zero_occ_atoms / pdbx_validate_close_contact / struct_conn
Revision 1.3Jan 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)47,2525
Polymers46,2911
Non-polymers9614
Water2,180121
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1070 Å2
ΔGint-20 kcal/mol
Surface area16320 Å2
MethodPISA
Unit cell
Length a, b, c (Å)109.442, 109.442, 84.515
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-7FE / ~{N}-[4-(2-chloranyl-5-methyl-pyrimidin-4-yl)phenyl]-2,4-bis(oxidanyl)-~{N}-[[4-(pyrrolidin-1-ylmethyl)phenyl]methyl]benzamide


Mass: 529.029 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H29ClN4O3
#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.: 2 / Source method: obtained synthetically / Formula: Cl
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 121 / 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: 3.16 Å3/Da / Density % sol: 61.03 %
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: Feb 10, 2011 / 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: 2.3→29.59 Å / Num. obs: 25546 / % possible obs: 99.4 % / Redundancy: 3.65 % / Rmerge(I) obs: 0.09 / Net I/σ(I): 7.1
Reflection shellResolution: 2.3→2.38 Å / Redundancy: 3.53 % / Rmerge(I) obs: 0.541 / Mean I/σ(I) obs: 1.5 / % possible all: 99

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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: 2.3→20 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.93 / SU B: 8.553 / SU ML: 0.189 / Cross valid method: THROUGHOUT / ESU R: 0.227 / ESU R Free: 0.205 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25178 1300 5.1 %RANDOM
Rwork0.19951 ---
obs0.20218 24244 99.35 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 54.98 Å2
Baniso -1Baniso -2Baniso -3
1-0.94 Å20.47 Å20 Å2
2--0.94 Å2-0 Å2
3----3.04 Å2
Refinement stepCycle: 1 / Resolution: 2.3→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2749 0 65 121 2935
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0192880
X-RAY DIFFRACTIONr_bond_other_d0.0020.022734
X-RAY DIFFRACTIONr_angle_refined_deg1.8581.9983897
X-RAY DIFFRACTIONr_angle_other_deg1.1613.0036243
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9465339
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.04924.063128
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.69515493
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.8981515
X-RAY DIFFRACTIONr_chiral_restr0.1160.2424
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0213183
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02637
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_it4.275.2251368
X-RAY DIFFRACTIONr_mcbond_other4.2275.2231367
X-RAY DIFFRACTIONr_mcangle_it6.1377.7971703
X-RAY DIFFRACTIONr_mcangle_other6.1367.81704
X-RAY DIFFRACTIONr_scbond_it4.9045.7261512
X-RAY DIFFRACTIONr_scbond_other4.9025.7261513
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other7.4848.3892195
X-RAY DIFFRACTIONr_long_range_B_refined10.8849.44612036
X-RAY DIFFRACTIONr_long_range_B_other10.88449.44711997
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.299→2.358 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.393 100 -
Rwork0.349 1752 -
obs--98.62 %

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