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- PDB-4hdc: Discovery of Selective and Potent Inhibitors of Gram-positive Bac... -

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Basic information

Entry
Database: PDB / ID: 4hdc
TitleDiscovery of Selective and Potent Inhibitors of Gram-positive Bacterial Thymidylate Kinase (TMK: Compound 41)
ComponentsThymidylate kinase
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Kinase / TMP / active site / TRANSFERASE-TRANSFERASE INHIBITOR complex
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-13Y / Thymidylate kinase
Similarity search - Component
Biological speciesStaphylococcus aureus subsp. aureus (bacteria)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.05 Å
AuthorsOlivier, N.B.
CitationJournal: J.Med.Chem. / Year: 2012
Title: Discovery of Selective and Potent Inhibitors of Gram-Positive Bacterial Thymidylate Kinase (TMK).
Authors: Martinez-Botella, G. / Breen, J.N. / Duffy, J.E. / Dumas, J. / Geng, B. / Gowers, I.K. / Green, O.M. / Guler, S. / Hentemann, M.F. / Hernandez-Juan, F.A. / Joseph-McCarthy, D. / Kawatkar, S. ...Authors: Martinez-Botella, G. / Breen, J.N. / Duffy, J.E. / Dumas, J. / Geng, B. / Gowers, I.K. / Green, O.M. / Guler, S. / Hentemann, M.F. / Hernandez-Juan, F.A. / Joseph-McCarthy, D. / Kawatkar, S. / Larsen, N.A. / Lazari, O. / Loch, J.T. / Macritchie, J.A. / McKenzie, A.R. / Newman, J.V. / Olivier, N.B. / Otterson, L.G. / Owens, A.P. / Read, J. / Sheppard, D.W. / Keating, T.A.
History
DepositionOct 2, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 24, 2012Provider: repository / Type: Initial release
Revision 1.1Jan 2, 2013Group: 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
Revision 1.3Apr 3, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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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)47,9614
Polymers46,9092
Non-polymers1,0522
Water2,936163
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1990 Å2
ΔGint-19 kcal/mol
Surface area18050 Å2
MethodPISA
Unit cell
Length a, b, c (Å)46.530, 90.736, 48.346
Angle α, β, γ (deg.)90.00, 101.44, 90.00
Int Tables number4
Space group name H-MP1211

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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 subsp. aureus (bacteria)
Strain: MW2 / Gene: SA0440, tmk / Plasmid: pET30a / Production host: Escherichia coli (E. coli) / Strain (production host): BL21-Codon + / References: UniProt: P65249, dTMP kinase
#2: Chemical ChemComp-13Y / 2-(3-chlorophenoxy)-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: 526.024 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H32ClN3O5
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 163 / 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: 2.13 Å3/Da / Density % sol: 42.32 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5
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 20 C 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 20 C 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., VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 140 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E+ SUPERBRIGHT / Wavelength: 1.54 Å
DetectorType: RIGAKU SATURN 944+ / Detector: CCD / Date: Nov 9, 2009 / Details: confocal
RadiationMonochromator: graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.05→40 Å / Num. obs: 23056 / % possible obs: 94.5 % / Redundancy: 2.4 % / Biso Wilson estimate: 32.48 Å2 / Rmerge(I) obs: 0.096 / Net I/σ(I): 8.9
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique allDiffraction-ID% possible all
2.05-2.122.30.3392.41050198
2.12-2.212.40.2623.21006198.7
2.21-2.312.40.2253.61014198.6
2.31-2.432.40.2284.4988197.6
2.43-2.582.30.2074.61012194.9
2.58-2.782.10.1725.61063191.1
2.78-3.0620.1356.11175186.1
3.06-3.52.50.089.5939195.3
3.5-4.412.50.06912918192.9

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Processing

Software
NameClassification
JDirectordata collection
AMoREphasing
BUSTERrefinement
XDSdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: In house apo state.

Resolution: 2.05→23.34 Å / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2508 1160 5.03 %RANDOM
Rwork0.2142 ---
all0.2161 24727 --
obs-23056 93.24 %-
Displacement parametersBiso mean: 36.55 Å2
Baniso -1Baniso -2Baniso -3
1--6.3835 Å20 Å2-10.3512 Å2
2--6.7917 Å20 Å2
3----0.4082 Å2
Refine analyzeLuzzati coordinate error obs: 0.298 Å
Refinement stepCycle: LAST / Resolution: 2.05→23.34 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3112 0 74 163 3349
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONo_bond_d0.01
X-RAY DIFFRACTIONo_angle_deg1.11
LS refinement shellResolution: 2.05→2.14 Å / Total num. of bins used: 12
RfactorNum. reflection% reflection
Rfree0.2346 129 -
Rwork0.2378 --
obs-2809 93.24 %

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