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- PDB-4qgg: TMK in complex with compound 46, 2-(3-CHLOROPHENOXY)-3-FLUORO-4-{... -

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Basic information

Entry
Database: PDB / ID: 4qgg
TitleTMK in complex with compound 46, 2-(3-CHLOROPHENOXY)-3-FLUORO-4-{(1R)-3-METHYL-1-[(3S)-3-(5-METHYL-2,4-DIOXO-3,4-DIHYDROPYRIMIDIN-1(2H)-YL)PIPERIDIN-1-YL]BUTYL}BENZOIC ACID
ComponentsThymidylate kinase
KeywordsTransferase/transferase inhibitor / thymidine monphosphate / soluble / Transferase-transferase inhibitor complex
Function / homology
Function and homology information


dUDP biosynthetic process / dTMP kinase / thymidylate kinase activity / dTDP biosynthetic process / dTTP biosynthetic process / phosphorylation / ATP binding / cytosol
Similarity search - Function
Thymidylate kinase, conserved site / Thymidylate kinase signature. / Thymidylate kinase / Thymidylate kinase-like domain / Thymidylate kinase / P-loop containing nucleotide triphosphate hydrolases / Rossmann fold / P-loop containing nucleoside triphosphate hydrolase / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-32C / Thymidylate kinase
Similarity search - Component
Biological speciesStaphylococcus aureus subsp. aureus (bacteria)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.62 Å
AuthorsOlivier, N.B.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Antibacterial inhibitors of gram-positive thymidylate kinase: structure-activity relationships and chiral preference of a new hydrophobic binding region.
Authors: Kawatkar, S.P. / Keating, T.A. / Olivier, N.B. / Breen, J.N. / Green, O.M. / Guler, S.Y. / Hentemann, M.F. / Loch, J.T. / McKenzie, A.R. / Newman, J.V. / Otterson, L.G. / Martinez-Botella, G.
History
DepositionMay 22, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 11, 2014Provider: repository / Type: Initial release
Revision 1.1Jul 2, 2014Group: Database references
Revision 1.2Feb 28, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / software / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _software.name / _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

Downloads & links

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Assembly

Deposited unit
A: Thymidylate kinase
B: Thymidylate kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,9974
Polymers46,9092
Non-polymers1,0882
Water3,099172
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1970 Å2
ΔGint-19 kcal/mol
Surface area17040 Å2
MethodPISA
Unit cell
Length a, b, c (Å)46.996, 91.042, 48.504
Angle α, β, γ (deg.)90.000, 100.630, 90.000
Int Tables number4
Space group name H-MP1211
Detailsbiological unit is a dimer. For molecule A the partern is x, y, z-1. for molecule B the partner is x, y, Z+1.

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Components

#1: Protein Thymidylate kinase / dTMP kinase


Mass: 23454.586 Da / Num. of mol.: 2 / Fragment: TMK / Mutation: none
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Staphylococcus aureus subsp. aureus (bacteria)
Strain: MRSA252 / Gene: SAR0483, tmk / Plasmid: pET28a / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 (DE3) / References: UniProt: Q6GJI9, dTMP kinase
#2: Chemical ChemComp-32C / 2-(3-chlorophenoxy)-3-fluoro-4-{(1R)-3-methyl-1-[(3S)-3-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)piperidin-1-yl]butyl}benzoic acid


Mass: 544.014 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H31ClFN3O5
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 172 / 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: 2.17 Å3/Da / Density % sol: 43.42 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: To obtain the inhibitor bound crystal form of TMK-S.aureus crystals were initially grown in the absence of compound using the sitting drop method at 293 K with a reservoir solution of 100 mM ...Details: To obtain the inhibitor bound crystal form of TMK-S.aureus crystals were initially grown in the absence of compound using the sitting drop method at 293 K with a reservoir solution of 100 mM PCPT (propionate-cacodylate-bistris propane buffer) pH 7-8, 21-24% PEG 3350, 200 mM Mg2Cl using 1:1 protein:reservoir solution with the protein solution at 13 mg/mL. Crystals were harvested and soaked overnight in a solution containing 100 mM PCPT, 35% PEG 3350, 200 mM Mg2Cl and 1-2 mM or compound from a 100 mM DMSO stock. After soaking the crystals were cryoprotected by soaking for 15 minutes in compound-soak solution supplemented with 20% ethylene glycol., VAPOR DIFFUSION, SITTING DROP
PH range: 7-8

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Data collection

DiffractionMean temperature: 140 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Aug 16, 2010 / Details: pixel
RadiationMonochromator: mirror / Protocol: SINGLE WAVELENGTH / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.621→91.042 Å / Num. all: 49913 / Num. obs: 49913 / % possible obs: 98.4 % / Redundancy: 3.4 % / Biso Wilson estimate: 25.32 Å2 / Rsym value: 0.033 / Net I/σ(I): 15.7
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRsym value% possible all
1.62-1.713.40.4831.62495472430.48398.2
1.71-1.813.50.292.72385968920.2998.4
1.81-1.943.30.1744.42118764220.17498
1.94-2.093.40.0997.72045860100.09998.2
2.09-2.293.40.05812.61902955800.05898.6
2.29-2.563.30.0416.41643950540.0499.1
2.56-2.963.50.03119.61534944400.03198.7
2.96-3.623.20.02621.41188937720.02698.5
3.62-5.133.30.0228.5958428710.0297.2
5.13-91.0423.20.0226.1527016290.0298.2

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Processing

Software
NameVersionClassificationNB
SCALA3.3.16data scaling
BUSTER-TNTBUSTER 2.11.5refinement
PDB_EXTRACT3.14data extraction
JDirectordata collection
PROCESSdata reduction
AMoREphasing
BUSTER2.11.5refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.62→47.67 Å / Cor.coef. Fo:Fc: 0.903 / Cor.coef. Fo:Fc free: 0.8923 / SU R Cruickshank DPI: 0.101 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.2222 2527 5.07 %RANDOM
Rwork0.2079 ---
obs0.2087 49834 97.92 %-
all-50892 --
Displacement parametersBiso max: 113.55 Å2 / Biso mean: 35.56 Å2 / Biso min: 16.65 Å2
Baniso -1Baniso -2Baniso -3
1--10.3576 Å20 Å2-16.7638 Å2
2--11.2057 Å20 Å2
3----0.8482 Å2
Refine analyzeLuzzati coordinate error obs: 0.33 Å
Refinement stepCycle: LAST / Resolution: 1.62→47.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3009 0 76 172 3257
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1086SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes82HARMONIC2
X-RAY DIFFRACTIONt_gen_planes471HARMONIC5
X-RAY DIFFRACTIONt_it3137HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion417SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3851SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d3137HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg4254HARMONIC21.06
X-RAY DIFFRACTIONt_omega_torsion3.14
X-RAY DIFFRACTIONt_other_torsion17.7
LS refinement shellResolution: 1.62→1.66 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.3425 174 4.89 %
Rwork0.3093 3386 -
all0.3109 3560 -
obs--97.92 %

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