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- PDB-4hxw: Pyrrolopyrimidine inhibitors of dna gyrase b and topoisomerase iv... -

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Basic information

Entry
Database: PDB / ID: 4hxw
TitlePyrrolopyrimidine inhibitors of dna gyrase b and topoisomerase iv, part i: structure guided discovery and optimization of dual targeting agents with potent, broad-spectrum enzymatic activity.
ComponentsDNA gyrase subunit B
KeywordsIsomerase/Isomerase inhibitor / ATP-binding / Nucleotide-binding / Topoisomerase / ATP-binding domain / Isomerase-Isomerase inhibitor complex
Function / homology
Function and homology information


DNA negative supercoiling activity / DNA topoisomerase (ATP-hydrolysing) / DNA topological change / DNA-templated DNA replication / chromosome / DNA binding / ATP binding / metal ion binding / cytoplasm
Similarity search - Function
DNA gyrase subunit B, TOPRIM domain / DNA gyrase, subunit B / 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. ...DNA gyrase subunit B, TOPRIM domain / DNA gyrase, subunit B / 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 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-1A0 / TERTIARY-BUTYL ALCOHOL / DNA gyrase subunit B
Similarity search - Component
Biological speciesEnterococcus faecalis (bacteria)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.69 Å
AuthorsBensen, D.C. / Trzoss, M. / Tari, L.W.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: Pyrrolopyrimidine inhibitors of DNA gyrase B (GyrB) and topoisomerase IV (ParE). Part I: Structure guided discovery and optimization of dual targeting agents with potent, broad-spectrum enzymatic activity.
Authors: Tari, L.W. / Trzoss, M. / Bensen, D.C. / Li, X. / Chen, Z. / Lam, T. / Zhang, J. / Creighton, C.J. / Cunningham, M.L. / Kwan, B. / Stidham, M. / Shaw, K.J. / Lightstone, F.C. / Wong, S.E. / ...Authors: Tari, L.W. / Trzoss, M. / Bensen, D.C. / Li, X. / Chen, Z. / Lam, T. / Zhang, J. / Creighton, C.J. / Cunningham, M.L. / Kwan, B. / Stidham, M. / Shaw, K.J. / Lightstone, F.C. / Wong, S.E. / Nguyen, T.B. / Nix, J. / Finn, J.
History
DepositionNov 12, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 13, 2013Provider: repository / Type: Initial release
Revision 1.1Feb 27, 2013Group: 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_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _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: DNA gyrase subunit B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,3373
Polymers23,8361
Non-polymers5012
Water4,648258
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)54.833, 58.757, 66.136
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein DNA gyrase subunit B


Mass: 23835.613 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Enterococcus faecalis (bacteria) / Strain: ATCC 700802 / V583 / Gene: EF_0005, gyrB / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: Q839Z1, EC: 5.99.1.3
#2: Chemical ChemComp-1A0 / (3R)-1-[5-chloro-6-ethyl-2-(pyrido[2,3-b]pyrazin-7-ylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-amine


Mass: 426.926 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H19ClN8S
#3: Chemical ChemComp-TBU / TERTIARY-BUTYL ALCOHOL / 2-METHYL-2-PROPANOL


Mass: 74.122 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 258 / 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: 2.23 Å3/Da / Density % sol: 44.96 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.6
Details: 25% (W/V) PEG 1500, 3% (V/V) T-BUTANOL, 20% (W/V) GLYCEROL, 20 MM CITRATE, pH 5.6 , VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 4.2.2 / Wavelength: 1
DetectorType: NOIR-1 / Detector: CCD / Date: Apr 25, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.68→23.26 Å / Num. all: 92704 / Num. obs: 23887 / % possible obs: 95.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Rmerge(I) obs: 0.046
Reflection shellResolution: 1.68→1.77 Å / Rmerge(I) obs: 0.231 / % possible all: 95.9

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Processing

Software
NameVersionClassification
REFMAC5.6.0117refinement
d*TREKdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.69→23.26 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.945 / SU B: 1.702 / SU ML: 0.058 / Cross valid method: THROUGHOUT / ESU R: 0.101 / ESU R Free: 0.098 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.20042 1221 5.1 %RANDOM
Rwork0.16995 ---
obs0.1715 22629 96.88 %-
all-92704 --
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 mean: 22.224 Å2
Baniso -1Baniso -2Baniso -3
1--0.16 Å20 Å20 Å2
2--0.01 Å20 Å2
3---0.16 Å2
Refinement stepCycle: LAST / Resolution: 1.69→23.26 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1510 0 34 258 1802
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.021581
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.291.9832148
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.1915193
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.62423.68476
X-RAY DIFFRACTIONr_dihedral_angle_3_deg10.55815264
X-RAY DIFFRACTIONr_dihedral_angle_4_deg11.91513
X-RAY DIFFRACTIONr_chiral_restr0.0760.2242
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0211195
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.689→1.733 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.3 72 -
Rwork0.264 1223 -
obs--76.85 %

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