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- PDB-4xwa: TMK from S.aureus in complex with the Piperidinyl Thymine class i... -

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Basic information

Entry
Database: PDB / ID: 4xwa
TitleTMK from S.aureus in complex with the Piperidinyl Thymine class inhibitor with a C5 ethyl-amine
ComponentsThymidylate kinase
KeywordsTRANSFERASE / TMK / kinase / antibacterial / piperidine / thymidine
Function / homology
Function and homology information


dTMP kinase / thymidylate kinase activity / dTDP biosynthetic process / dTTP biosynthetic process / ATP binding
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-43N / Thymidylate kinase
Similarity search - Component
Biological speciesStaphylococcus aureus (bacteria)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.89 Å
AuthorsOlivier, N.B.
CitationJournal: Bioorg Med Chem Lett / Year: 2015
Title: A highly potent antibacterial inhibitor of Gram-positive bacterial thymidylate kinase (TMK): SAR of piperidinyl thymines at position C5 and L1
Authors: Guler, S.Y. / Martinez-Botella, G. / Breen, J. / Kawatkar, S. / Loch, J. / Olivier, N.B. / Wang, H. / Keating, T. / Otterson, L.
History
DepositionJan 28, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Feb 11, 2015Provider: repository / Type: Initial release
Revision 1.1May 1, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / diffrn_radiation_wavelength / 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: Thymidylate kinase
B: Thymidylate kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)48,0874
Polymers46,9092
Non-polymers1,1782
Water5,603311
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area560 Å2
ΔGint-0 kcal/mol
Surface area19200 Å2
MethodPISA
Unit cell
Length a, b, c (Å)45.483, 89.806, 50.875
Angle α, β, γ (deg.)90.000, 99.290, 90.000
Int Tables number4
Space group name H-MP1211
Detailsbiological unit is the same as asym.

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Components

#1: Protein Thymidylate kinase / dTMP kinase


Mass: 23454.586 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Staphylococcus aureus (strain Mu3 / ATCC 700698) (bacteria)
Gene: tmk, SAHV_0479 / Production host: Escherichia coli BL21 (bacteria) / References: UniProt: A7WYM2, dTMP kinase
#2: Chemical ChemComp-43N / 2-(3-chlorophenoxy)-6-(ethylamino)-4-[(R)-[(3S)-3-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)piperidin-1-yl](phenyl)methyl]benzoic acid


Mass: 589.081 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C32H33ClN4O5
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 311 / 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: 2.19 Å3/Da / Density % sol: 43.73 % / Description: bars
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7
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 TK-666 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. Cryoprotected crystals were mounted on nylon loops and flash-cooled in liquid nitrogen.
PH range: 7-8

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E+ SUPERBRIGHT / Wavelength: 1.54 Å
DetectorType: RIGAKU SATURN 944+ / Detector: CCD / Date: Jun 6, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 1.887→33.831 Å / Num. all: 31072 / Num. obs: 31072 / % possible obs: 95.9 % / Redundancy: 2.8 % / Biso Wilson estimate: 23.81 Å2 / Rpim(I) all: 0.029 / Rrim(I) all: 0.053 / Rsym value: 0.037 / Net I/av σ(I): 15.813 / Net I/σ(I): 16.2 / Num. measured all: 88375
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRpim(I) allRsym valueNet I/σ(I) obs% possible all
1.89-1.991.90.2123.6755639340.2040.2123.684.4
1.99-2.112.70.1614.81141842930.1290.1616.296
2.11-2.262.90.17.71181340580.0780.19.597
2.26-2.4430.07310.51151038530.0560.07312.698.3
2.44-2.673.10.059131103235840.0450.05914.899.4
2.67-2.983.10.04516.51015932610.0340.04518.299.6
2.98-3.443.10.03221.7893328590.0250.03224.699.3
3.44-4.2230.02526.2706623570.0190.02534.396.2
4.22-5.973.10.02227.8567618290.0160.02238.296.9
5.97-33.8313.10.01826.7321210440.0140.01838.898

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
XDS3.3.15data reduction
AMoREphasing
BUSTER2.11.6refinement
PDB_EXTRACT3.15data extraction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: apo-state structure

Resolution: 1.89→33.83 Å / Cor.coef. Fo:Fc: 0.94 / Cor.coef. Fo:Fc free: 0.9136 / SU R Cruickshank DPI: 0.169 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.173 / SU Rfree Blow DPI: 0.149 / SU Rfree Cruickshank DPI: 0.148
RfactorNum. reflection% reflectionSelection details
Rfree0.2291 1574 5.09 %RANDOM
Rwork0.1925 ---
obs0.1944 30902 95.72 %-
Displacement parametersBiso max: 114.56 Å2 / Biso mean: 27.39 Å2 / Biso min: 9.27 Å2
Baniso -1Baniso -2Baniso -3
1--3.3397 Å20 Å2-5.344 Å2
2--3.1018 Å20 Å2
3---0.2379 Å2
Refine analyzeLuzzati coordinate error obs: 0.228 Å
Refinement stepCycle: final / Resolution: 1.89→33.83 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3124 0 84 311 3519
Biso mean--20.13 40.29 -
Num. residues----398
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1148SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes89HARMONIC2
X-RAY DIFFRACTIONt_gen_planes497HARMONIC5
X-RAY DIFFRACTIONt_it3276HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion434SEMIHARMONIC5
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_contact4110SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d3276HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg4442HARMONIC21.06
X-RAY DIFFRACTIONt_omega_torsion3.17
X-RAY DIFFRACTIONt_other_torsion17.61
LS refinement shellResolution: 1.89→1.95 Å / Total num. of bins used: 16
RfactorNum. reflection% reflection
Rfree0.3215 112 4.77 %
Rwork0.2595 2235 -
all0.2625 2347 -
obs--95.72 %

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