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- PDB-4hlc: Sulfonylpiperidines as Novel, Antibacterial Inhibitors of Gram-Po... -

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Basic information

Entry
Database: PDB / ID: 4hlc
TitleSulfonylpiperidines as Novel, Antibacterial Inhibitors of Gram-Positive Thymidylate Kinase (TMK): Compound 5
ComponentsThymidylate kinase
Keywordstransferase/transferase inhibitor / TMK / kinase / thymidylate kinase / MRSA / pipiridine / 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-T05 / Thymidylate kinase
Similarity search - Component
Biological speciesStaphylococcus aureus subsp. aureus (bacteria)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.55 Å
AuthorsBoriack-Sjodin, A. / Olivier, N.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: Sulfonylpiperidines as novel, antibacterial inhibitors of Gram-positive thymidylate kinase (TMK).
Authors: Martinez-Botella, G. / Loch, J.T. / Green, O.M. / Kawatkar, S.P. / Olivier, N.B. / Boriack-Sjodin, P.A. / Keating, T.A.
History
DepositionOct 16, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 31, 2012Provider: repository / Type: Initial release
Revision 1.1Jan 2, 2013Group: Database references
Revision 1.2Nov 29, 2023Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_related / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_related.db_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

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)47,9084
Polymers46,9092
Non-polymers9992
Water5,332296
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1980 Å2
ΔGint-18 kcal/mol
Surface area17690 Å2
MethodPISA
Unit cell
Length a, b, c (Å)46.200, 90.970, 48.330
Angle α, β, γ (deg.)90.00, 102.85, 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 / Fragment: TMK
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Staphylococcus aureus subsp. aureus (bacteria)
Strain: MRSA252 / Gene: SAR0483, tmk / Plasmid: pET30 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 (DE3) codon + / References: UniProt: Q6GJI9, dTMP kinase
#2: Chemical ChemComp-T05 / 4-{[(3S)-3-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)piperidin-1-yl]sulfonyl}-2-(3-methylphenoxy)benzoic acid


Mass: 499.536 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H25N3O7S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 296 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.11 Å3/Da / Density % sol: 41.73 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.8
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. , VAPOR DIFFUSION, SITTING DROP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 0.98 Å
DetectorType: RAYONIX MX225HE / Detector: CCD / Date: Oct 23, 2009 / Details: mirrors
RadiationMonochromator: Diamond (111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 1.55→42 Å / Num. all: 56013 / Num. obs: 55957 / % possible obs: 99.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.6 % / Biso Wilson estimate: 20.3 Å2 / Rmerge(I) obs: 0.054 / Net I/σ(I): 14.3
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsDiffraction-ID% possible all
1.55-1.643.50.3712.3199.9
1.64-1.743.60.2483.1199.9
1.74-1.863.60.1554.8199.9
1.86-2.013.60.1076.4199.9
2.01-2.23.60.0817.9199.9
2.2-2.463.60.05611.5199.8
2.46-2.843.60.04613.3199.7
2.84-3.473.50.05410.5199.6
3.47-4.913.40.03716.1199.4
4.91-423.70.02128.8199.2

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Processing

Software
NameVersionClassification
CBASSdata collection
AMoREphasing
BUSTER2.11.2refinement
XDSdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: in-house apo-state coordinates

Resolution: 1.55→41.84 Å / Cor.coef. Fo:Fc: 0.9429 / Cor.coef. Fo:Fc free: 0.9329 / SU R Cruickshank DPI: 0.08 / Cross valid method: THROUGHOUT / σ(F): 0
Details: Data reduction was accomplished by employing the AutoPROC toolbox and the structure determined by molecular replacement with AMoRE using an apo-state model of S. aureus TMK. COOT was used to ...Details: Data reduction was accomplished by employing the AutoPROC toolbox and the structure determined by molecular replacement with AMoRE using an apo-state model of S. aureus TMK. COOT was used to inspect the model and electron density and BUSTER or REFMAC were used for macromolecular refinement calculations. Geometry of the model was analyzed with MolProbity and stereochemistry of the compound analyzed with MOGUL.
RfactorNum. reflection% reflectionSelection details
Rfree0.1985 2839 5.08 %RANDOM
Rwork0.1789 ---
obs0.1799 55928 99.22 %-
all-56367 --
Displacement parametersBiso mean: 26.32 Å2
Baniso -1Baniso -2Baniso -3
1--3.4139 Å20 Å2-7.2863 Å2
2--4.3104 Å20 Å2
3----0.8965 Å2
Refine analyzeLuzzati coordinate error obs: 0.175 Å
Refinement stepCycle: LAST / Resolution: 1.55→41.84 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3086 0 70 296 3452
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.013286HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.14467HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1171SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes89HARMONIC2
X-RAY DIFFRACTIONt_gen_planes501HARMONIC5
X-RAY DIFFRACTIONt_it3286HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.43
X-RAY DIFFRACTIONt_other_torsion17.73
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion432SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies10HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact4117SEMIHARMONIC4
LS refinement shellResolution: 1.55→1.59 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2391 197 5.29 %
Rwork0.2184 3529 -
all0.2195 3726 -
obs--99.22 %

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