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- PDB-4lpb: Crystal structure of a topoisomerase ATPase inhibitor -

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Basic information

Entry
Database: PDB / ID: 4lpb
TitleCrystal structure of a topoisomerase ATPase inhibitor
ComponentsTopoisomerase IV subunit B
KeywordsISOMERASE/ISOMERASE INHIBITOR / protein-inhibitor complex / ATP binding / structure-based drug design / antimicrobial / virtual screen / ATP binding domain / ISOMERASE-ISOMERASE INHIBITOR complex
Function / homology
Function and homology information


DNA topoisomerase type II (double strand cut, ATP-hydrolyzing) activity / DNA topoisomerase (ATP-hydrolysing) / DNA topological change / chromosome segregation / chromosome / DNA binding / ATP binding / metal ion binding
Similarity search - Function
DNA topoisomerase 4 subunit B, Firmicutes/Mollicutes / DNA topoisomerase, type IIA, subunit B / DNA gyrase B subunit, C-terminal / DNA gyrase B subunit, carboxyl terminus / DNA topoisomerase, type IIA, subunit B, domain 2 / DNA gyrase B / DNA topoisomerase, type IIA / DNA topoisomerase, type IIA, conserved site / DNA topoisomerase II signature. / TopoisomeraseII ...DNA topoisomerase 4 subunit B, Firmicutes/Mollicutes / DNA topoisomerase, type IIA, subunit B / DNA gyrase B subunit, C-terminal / DNA gyrase B subunit, carboxyl terminus / DNA topoisomerase, type IIA, subunit B, domain 2 / DNA gyrase B / DNA topoisomerase, type IIA / DNA topoisomerase, type IIA, conserved site / DNA topoisomerase II signature. / TopoisomeraseII / DNA topoisomerase, type IIA, subunit B, C-terminal / Toprim domain / DNA topoisomerase, type IIA-like domain superfamily / Toprim domain profile. / TOPRIM domain / Histidine kinase-like ATPase, C-terminal domain / Heat Shock Protein 90 / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / Histidine kinase-like ATPases / Histidine kinase/HSP90-like ATPase / Histidine kinase/HSP90-like ATPase superfamily / Ribosomal protein S5 domain 2-type fold, subgroup / Ribosomal protein S5 domain 2-type fold / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-1YP / DNA topoisomerase 4 subunit B
Similarity search - Component
Biological speciesStreptococcus pneumoniae (bacteria)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.75 Å
AuthorsBoriack-Sjodin, A.
CitationJournal: J.Med.Chem. / Year: 2013
Title: Fragment-to-Hit-to-Lead Discovery of a Novel Pyridylurea Scaffold of ATP Competitive Dual Targeting Type II Topoisomerase Inhibiting Antibacterial Agents.
Authors: Basarab, G.S. / Manchester, J.I. / Bist, S. / Boriack-Sjodin, P.A. / Dangel, B. / Illingworth, R. / Sherer, B.A. / Sriram, S. / Uria-Nickelsen, M. / Eakin, A.E.
History
DepositionJul 15, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 30, 2013Provider: repository / Type: Initial release
Revision 1.1Jan 15, 2014Group: Database references
Revision 1.2Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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

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Assembly

Deposited unit
A: Topoisomerase IV subunit B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,0782
Polymers24,6011
Non-polymers4771
Water2,162120
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)73.411, 94.706, 61.180
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-495-

HOH

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Components

#1: Protein Topoisomerase IV subunit B


Mass: 24600.723 Da / Num. of mol.: 1 / Fragment: ATPase domain, UNP residues 1-226
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Streptococcus pneumoniae (bacteria) / Strain: ATCC BAA-255 / R6 / Gene: parE, spr0756 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: Q8DQB5, EC: 5.99.1.3
#2: Chemical ChemComp-1YP / 1-ethyl-3-{5'-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]-3,3'-bipyridin-6-yl}urea


Mass: 477.420 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H14F3N7O3S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 120 / 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: 2.16 Å3/Da / Density % sol: 43.09 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 18-25% Peg4000, 0.2M Ammonium Acetate, 0.1M MIB pH 7, hanging drop, inhibitor soak, temperature 293K, VAPOR DIFFUSION, HANGING DROP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 1 Å
DetectorType: RAYONIX MX-225 / Detector: CCD / Date: Oct 12, 2007 / Details: monochromator
RadiationMonochromator: Diamond(111) crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.608→22.092 Å / Num. all: 21859 / Num. obs: 21859 / % possible obs: 99.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 7.1 % / Rmerge(I) obs: 0.093 / Rsym value: 0.093 / Net I/σ(I): 14.7
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRsym value% possible all
1.75-1.847.20.5771.22256731520.577100
1.84-1.967.20.3442.12126429580.344100
1.96-2.097.20.2063.42035628280.206100
2.09-2.267.20.1494.81892426280.149100
2.26-2.477.20.1146.21737224100.114100
2.47-2.777.20.0916.81588222040.091100
2.77-3.27.20.0758.71409819620.075100
3.2-3.917.10.0639.81181716580.063100
3.91-5.536.90.05710.6915013210.057100
5.53-22.0926.30.05211.846797380.05296.4

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
SCALA3.2.21data scaling
AMoREphasing
REFMAC5.2.0019refinement
PDB_EXTRACT3.11data extraction
MOSFLMdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.75→22.08 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.941 / Occupancy max: 1 / Occupancy min: 0.5 / SU B: 4.135 / SU ML: 0.068 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.12 / ESU R Free: 0.114 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2236 1117 5.1 %RANDOM
Rwork0.1936 ---
obs0.1951 21842 99.9 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso max: 56.78 Å2 / Biso mean: 22.675 Å2 / Biso min: 15.58 Å2
Baniso -1Baniso -2Baniso -3
1-0.08 Å20 Å20 Å2
2---0.56 Å20 Å2
3---0.49 Å2
Refinement stepCycle: LAST / Resolution: 1.75→22.08 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1485 0 33 120 1638
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0211599
X-RAY DIFFRACTIONr_bond_other_d0.0010.021031
X-RAY DIFFRACTIONr_angle_refined_deg1.0791.9692175
X-RAY DIFFRACTIONr_angle_other_deg0.77132526
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.6565201
X-RAY DIFFRACTIONr_dihedral_angle_2_deg29.43424.11868
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.32715270
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.423159
X-RAY DIFFRACTIONr_chiral_restr0.0540.2246
X-RAY DIFFRACTIONr_gen_planes_refined0.0020.021838
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02314
X-RAY DIFFRACTIONr_nbd_refined0.1950.2305
X-RAY DIFFRACTIONr_nbd_other0.1820.21067
X-RAY DIFFRACTIONr_nbtor_refined0.1690.2819
X-RAY DIFFRACTIONr_nbtor_other0.080.2801
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.0870.295
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1350.23
X-RAY DIFFRACTIONr_symmetry_vdw_other0.1040.219
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.0940.28
X-RAY DIFFRACTIONr_mcbond_it0.4461.51019
X-RAY DIFFRACTIONr_mcbond_other0.0691.5408
X-RAY DIFFRACTIONr_mcangle_it0.68421592
X-RAY DIFFRACTIONr_scbond_it1.1133659
X-RAY DIFFRACTIONr_scangle_it1.74.5583
LS refinement shellResolution: 1.75→1.795 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.236 79 -
Rwork0.218 1501 -
all-1580 -
obs--100 %
Refinement TLS params.Method: refined / Origin x: 23.443 Å / Origin y: 32.137 Å / Origin z: 0.526 Å
111213212223313233
T-0.0688 Å2-0.0074 Å20.0089 Å2--0.0368 Å20.0048 Å2---0.0378 Å2
L0.654 °2-0.2622 °20.0174 °2-1.4715 °2-0.2305 °2--1.187 °2
S-0.0258 Å °0.0131 Å °-0.0373 Å °-0.0102 Å °-0.0252 Å °-0.0775 Å °0.0786 Å °0.0443 Å °0.051 Å °

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