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- PDB-6tmp: Rapid optimisation of fragments and hits to lead compounds from s... -

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Basic information

Entry
Database: PDB / ID: 6tmp
TitleRapid optimisation of fragments and hits to lead compounds from screening of crude reaction mixtures
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 / 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
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 / Histidine kinase domain / Histidine kinase domain profile. / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / Histidine kinase-like ATPases / Histidine kinase/HSP90-like ATPase superfamily
Similarity search - Domain/homology
Chem-NN8 / Chem-TF3 / [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MIR / Resolution: 2.076 Å
AuthorsBaker, L.M. / Aimon, A. / Murray, J.B. / Surgenor, A.E. / Matassova, N. / Roughley, S.D. / von Delft, F. / Hubbard, R.E.
CitationJournal: Commun Chem / Year: 2020
Title: Rapid optimisation of fragments and hits to lead compounds from screening of crude reaction mixtures
Authors: Baker, L.M. / Aimon, A. / Murray, J.B. / Surgenor, A.E. / Matassova, N. / Roughley, S.D. / Collins, P.M. / Krojer, T. / von Delft, F. / Hubbard, R.E.
History
DepositionDec 5, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 14, 2020Provider: repository / Type: Initial release
Revision 1.1May 15, 2024Group: Data collection / Database references / Derived calculations
Category: atom_type / chem_comp_atom ...atom_type / chem_comp_atom / chem_comp_bond / database_2
Item: _atom_type.pdbx_N_electrons / _atom_type.pdbx_scat_Z ..._atom_type.pdbx_N_electrons / _atom_type.pdbx_scat_Z / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)45,4394
Polymers44,6481
Non-polymers7923
Water2,522140
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area850 Å2
ΔGint-8 kcal/mol
Surface area16120 Å2
MethodPISA
Unit cell
Length a, b, c (Å)109.292, 109.292, 83.654
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number172
Space group name H-MP64
Components on special symmetry positions
IDModelComponents
11AAA-339-

PHE

21AAA-339-

PHE

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Components

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


Mass: 44647.730 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDK2, PDHK2 / Plasmid: pET28a / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): pLysS
References: UniProt: Q15119, [pyruvate dehydrogenase (acetyl-transferring)] kinase
#2: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#3: Chemical ChemComp-NN8 / [2,4-bis(oxidanyl)phenyl]-[(1~{R})-6,7-dimethoxy-1-pyridin-3-yl-3,4-dihydro-1~{H}-isoquinolin-2-yl]methanone


Mass: 406.431 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H22N2O5 / Feature type: SUBJECT OF INVESTIGATION
#4: 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
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 140 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 3.23 Å3/Da / Density % sol: 61.92 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 5.8
Details: 0.1 M Sodium acetate pH 5.8 0.125 M Magnesium chloride

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.91587 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Oct 10, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91587 Å / Relative weight: 1
ReflectionResolution: 2.076→94.65 Å / Num. obs: 19985 / % possible obs: 93.9 % / Redundancy: 10.2 % / CC1/2: 1 / Rmerge(I) obs: 0.092 / Net I/σ(I): 16.8
Reflection shellResolution: 2.076→2.344 Å / Redundancy: 9.2 % / Rmerge(I) obs: 1.197 / Mean I/σ(I) obs: 1.9 / Num. unique obs: 1000 / CC1/2: 0.747 / % possible all: 76.2

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
xia2data reduction
Aimlessdata scaling
REFMACphasing
RefinementMethod to determine structure: MIR / Resolution: 2.076→94.65 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.922 / Cross valid method: FREE R-VALUE / ESU R: 0.281 / ESU R Free: 0.24
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2401 934 4.674 %
Rwork0.1719 --
all0.175 --
obs-19984 55.128 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 47.262 Å2
Baniso -1Baniso -2Baniso -3
1-0.08 Å20.04 Å20 Å2
2--0.08 Å2-0 Å2
3----0.259 Å2
Refinement stepCycle: LAST / Resolution: 2.076→94.65 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2766 0 56 140 2962
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0132907
X-RAY DIFFRACTIONr_bond_other_d0.0340.0172690
X-RAY DIFFRACTIONr_angle_refined_deg1.6171.6583935
X-RAY DIFFRACTIONr_angle_other_deg2.4061.5816252
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.5865345
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.12122.517147
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.96315500
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.3121515
X-RAY DIFFRACTIONr_chiral_restr0.0730.2367
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.023186
X-RAY DIFFRACTIONr_gen_planes_other0.0090.02610
X-RAY DIFFRACTIONr_nbd_refined0.2280.2659
X-RAY DIFFRACTIONr_symmetry_nbd_other0.2250.22512
X-RAY DIFFRACTIONr_nbtor_refined0.1790.21403
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0750.21309
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1680.2129
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0980.21
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2090.222
X-RAY DIFFRACTIONr_nbd_other0.2630.254
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1080.210
X-RAY DIFFRACTIONr_mcbond_it4.3074.8041380
X-RAY DIFFRACTIONr_mcbond_other4.2894.7971379
X-RAY DIFFRACTIONr_mcangle_it6.3617.1761719
X-RAY DIFFRACTIONr_mcangle_other6.3697.1831720
X-RAY DIFFRACTIONr_scbond_it4.7125.2891527
X-RAY DIFFRACTIONr_scbond_other4.715.2911528
X-RAY DIFFRACTIONr_scangle_it7.2917.7262214
X-RAY DIFFRACTIONr_scangle_other7.2897.7292215
X-RAY DIFFRACTIONr_lrange_it9.70456.1283327
X-RAY DIFFRACTIONr_lrange_other9.71856.0663307
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc work% reflection obs (%)WRfactor RworkFsc free
2.04-2.09300.424200.42426640.6350.75080.514
2.093-2.150.09720.285520.27326280.7662.05480.3730.919
2.15-2.2120.43260.2961390.30224980.7495.80460.3170.687
2.212-2.2810.384160.2833380.28724760.79414.29730.3080.768
2.281-2.3550.294210.2554880.25723560.80621.60440.2660.835
2.355-2.4380.326280.2515960.25423140.81826.96630.240.824
2.438-2.530.339310.2387330.24222350.84234.18340.2240.817
2.53-2.6330.283490.2599970.2621400.8348.87850.2420.846
2.633-2.750.323820.23515170.23920540.85977.84810.2110.809
2.75-2.8840.2721040.22918520.23119640.86999.59270.2040.851
2.884-3.040.304730.21318020.21718780.8999.84030.1830.846
3.04-3.2240.297730.19316910.19817660.91799.88670.1690.891
3.224-3.4470.257830.18215930.18616760.9341000.1640.915
3.447-3.7220.196760.15914740.1615500.951000.1430.94
3.722-4.0770.211770.14513520.14914310.96199.86020.1340.947
4.077-4.5570.178590.12812390.1312980.9691000.1210.96
4.557-5.260.19450.12611120.12811570.971000.1230.959
5.26-6.4370.313450.1579220.1639670.9541000.1560.918
6.437-9.0830.237440.157200.1557640.9621000.1550.947
9.083-94.650.181200.1774130.1774340.96399.76960.2120.962

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