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

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Basic information

Entry
Database: PDB / ID: 6tmq
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 / 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
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 / Histidine kinase/HSP90-like ATPase superfamily
Similarity search - Domain/homology
Chem-NMW / Chem-TF3 / [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MIR / Resolution: 2.112 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)45,4934
Polymers44,6481
Non-polymers8453
Water2,702150
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area960 Å2
ΔGint1 kcal/mol
Surface area16270 Å2
MethodPISA
Unit cell
Length a, b, c (Å)110.368, 110.368, 83.863
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

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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-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
#3: Chemical ChemComp-NMW / [2,4-bis(oxidanyl)phenyl]-[(1~{S})-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-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 150 / 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: 3.3 Å3/Da / Density % sol: 62.75 %
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: 2.112→63.038 Å / Num. obs: 19218 / % possible obs: 83.3 % / Redundancy: 10.1 % / CC1/2: 0.999 / Rmerge(I) obs: 0.127 / Net I/σ(I): 13.8
Reflection shellResolution: 2.112→2.324 Å / Rmerge(I) obs: 1.857 / Mean I/σ(I) obs: 1.5 / Num. unique obs: 960 / CC1/2: 0.571 / % possible all: 69.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
xia2data reduction
Aimlessdata scaling
REFMACphasing
RefinementMethod to determine structure: MIR / Resolution: 2.112→63.038 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.913 / Cross valid method: FREE R-VALUE / ESU R: 0.305 / ESU R Free: 0.242
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2343 889 4.626 %
Rwork0.1758 --
all0.178 --
obs-19218 52.055 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 45.574 Å2
Baniso -1Baniso -2Baniso -3
1--0.14 Å2-0.07 Å2-0 Å2
2---0.14 Å20 Å2
3---0.454 Å2
Refinement stepCycle: LAST / Resolution: 2.112→63.038 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2735 0 59 150 2944
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0132870
X-RAY DIFFRACTIONr_bond_other_d0.0340.0172651
X-RAY DIFFRACTIONr_angle_refined_deg1.5311.6583885
X-RAY DIFFRACTIONr_angle_other_deg2.3631.586157
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.995338
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.58122.534146
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.4315492
X-RAY DIFFRACTIONr_dihedral_angle_4_deg23.1451515
X-RAY DIFFRACTIONr_chiral_restr0.0730.2363
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.023139
X-RAY DIFFRACTIONr_gen_planes_other0.0080.02601
X-RAY DIFFRACTIONr_nbd_refined0.2180.2629
X-RAY DIFFRACTIONr_symmetry_nbd_other0.2240.22384
X-RAY DIFFRACTIONr_nbtor_refined0.1730.21391
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0720.21216
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1540.2131
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0370.21
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2630.215
X-RAY DIFFRACTIONr_nbd_other0.230.251
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1780.211
X-RAY DIFFRACTIONr_mcbond_it3.4934.6391358
X-RAY DIFFRACTIONr_mcbond_other3.464.6371357
X-RAY DIFFRACTIONr_mcangle_it5.3046.9291691
X-RAY DIFFRACTIONr_mcangle_other5.3046.9331692
X-RAY DIFFRACTIONr_scbond_it3.8965.1231512
X-RAY DIFFRACTIONr_scbond_other3.8955.1231513
X-RAY DIFFRACTIONr_scangle_it6.37.5062193
X-RAY DIFFRACTIONr_scangle_other6.2987.5062194
X-RAY DIFFRACTIONr_lrange_it8.88254.7813261
X-RAY DIFFRACTIONr_lrange_other8.89854.7543250
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)Rfactor allFsc freeFsc workWRfactor Rwork
2.042-2.0950027020
2.095-2.1520.15330.2478626433.36740.2420.8790.8560.251
2.152-2.2150.227120.26323625829.6050.2610.8090.8190.265
2.215-2.2830.379160.296287249012.16870.3010.7950.7880.309
2.283-2.3580.294220.244569243824.24120.2460.8440.8350.242
2.358-2.440.33280.24692234330.72980.2430.8430.8490.233
2.44-2.5330.261450.225864226340.16790.2270.8460.860.217
2.533-2.6360.339460.281884218542.56290.2840.8020.830.275
2.636-2.7530.362470.235848209842.65970.2410.8280.8830.216
2.753-2.8870.2781050.2141909201599.95040.2170.8690.90.193
2.887-3.0430.256810.202181618971000.2040.8880.9080.181
3.043-3.2280.273770.194174218191000.1970.9070.9220.172
3.228-3.450.244600.1881315168981.40910.190.9170.9320.176
3.45-3.7260.247610.1741344157489.2630.1770.9240.940.163
3.726-4.0810.204690.1491247147289.40220.1520.9460.9610.145
4.081-4.5620.169650.126125513201000.1280.9630.9720.13
4.562-5.2660.174430.126113511781000.1280.960.9720.137
5.266-6.4440.307450.1759479921000.180.9070.9470.189
6.444-9.0930.194460.1697337791000.1710.9430.950.19
9.093-95.5810.232200.21342044299.54750.2140.9230.9320.237

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