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

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Basic information

Entry
Database: PDB / ID: 4hym
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.
ComponentsTopoisomerase IV, subunit B
KeywordsIsomerase/Isomerase inhibitor / ATP-binding / Nucleotide-binding / Topoisomerase / 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 IV, subunit B, Gram-negative / 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 ...DNA topoisomerase IV, subunit B, Gram-negative / 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 / Ribosomal Protein S5; domain 2 - #10 / Toprim domain profile. / TOPRIM domain / Ribosomal Protein S5; domain 2 / 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-CJC / DNA topoisomerase 4 subunit B / :
Similarity search - Component
Biological speciesFrancisella tularensis subsp. holarctica LVS (bacteria)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsBensen, D.C. / Creighton, C.J. / Kwan, B. / 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 13, 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_sheet / 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_sheet.number_strands / _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
B: Topoisomerase IV, subunit B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)88,3443
Polymers87,9022
Non-polymers4431
Water11,422634
1
A: Topoisomerase IV, subunit B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,3942
Polymers43,9511
Non-polymers4431
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Topoisomerase IV, subunit B


Theoretical massNumber of molelcules
Total (without water)43,9511
Polymers43,9511
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)44.164, 130.282, 80.270
Angle α, β, γ (deg.)90.00, 98.12, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Topoisomerase IV, subunit B /


Mass: 43950.766 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Francisella tularensis subsp. holarctica LVS (bacteria)
Strain: LVS / Gene: FTL_1726 / Production host: Escherichia coli (E. coli)
References: UniProt: Q2A1P5, UniProt: A0A0J9WZF0*PLUS, EC: 5.99.1.3
#2: Chemical ChemComp-CJC / 7-({4-[(3R)-3-aminopyrrolidin-1-yl]-5-chloro-6-ethyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl}sulfanyl)pyrido[2,3-b]pyrazin-2(1H)-one


Mass: 442.925 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H19ClN8OS
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 634 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsTHE RESIDUE AT THIS POSITION INDICATES A NATURAL VARIANT

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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: 2.6 Å3/Da / Density % sol: 52.71 %
Crystal growTemperature: 277 K / pH: 5.4
Details: 10% PEG 4000, 10% isopropanol, 100 mM citrate , pH 5.4, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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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: Jul 13, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.9→43.43 Å / Num. obs: 70176 / % possible obs: 99.4 % / Rmerge(I) obs: 0.082 / Net I/σ(I): 7.2
Reflection shellResolution: 1.9→1.97 Å / Rmerge(I) obs: 0.414 / Mean I/σ(I) obs: 2.1 / % possible all: 99.1

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Processing

Software
NameVersionClassification
REFMAC5.6.0117refinement
d*TREKdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.9→43.43 Å / Cor.coef. Fo:Fc: 0.936 / Cor.coef. Fo:Fc free: 0.918 / SU B: 3.636 / SU ML: 0.108 / Cross valid method: THROUGHOUT / ESU R: 0.158 / ESU R Free: 0.151 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.276 3543 5.1 %RANDOM
Rwork0.238 ---
obs0.24 66593 99.4 %-
all-70136 --
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: 37.92 Å2
Baniso -1Baniso -2Baniso -3
1--0.97 Å20 Å20.26 Å2
2--1.15 Å20 Å2
3----0.11 Å2
Refinement stepCycle: LAST / Resolution: 1.9→43.43 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4637 0 30 634 5301
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.024774
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.5521.9726451
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.6895586
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.6826210
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.32315892
X-RAY DIFFRACTIONr_dihedral_angle_4_deg6.6361511
X-RAY DIFFRACTIONr_chiral_restr0.1220.2731
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0213506
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: 1.9→1.95 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.335 250 -
Rwork0.304 4830 -
obs--98.97 %

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