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- PDB-4hz5: Pyrrolopyrimidine inhibitors of dna gyrase b and topoisomerase iv... -

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Basic information

Entry
Database: PDB / ID: 4hz5
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 topoisomerase IV, B subunit
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 / 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 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-19Y / DNA topoisomerase 4 subunit B
Similarity search - Component
Biological speciesEnterococcus faecalis (bacteria)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsBensen, D.C. / Creighton, C.J. / 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 14, 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 topoisomerase IV, B subunit
B: DNA topoisomerase IV, B subunit
C: DNA topoisomerase IV, B subunit
D: DNA topoisomerase IV, B subunit
E: DNA topoisomerase IV, B subunit
F: DNA topoisomerase IV, B subunit
G: DNA topoisomerase IV, B subunit
H: DNA topoisomerase IV, B subunit
J: DNA topoisomerase IV, B subunit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)216,55117
Polymers214,0369
Non-polymers2,5158
Water1,06359
1
A: DNA topoisomerase IV, B subunit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,0962
Polymers23,7821
Non-polymers3141
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: DNA topoisomerase IV, B subunit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,0962
Polymers23,7821
Non-polymers3141
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: DNA topoisomerase IV, B subunit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,0962
Polymers23,7821
Non-polymers3141
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: DNA topoisomerase IV, B subunit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,0962
Polymers23,7821
Non-polymers3141
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
5
E: DNA topoisomerase IV, B subunit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,0962
Polymers23,7821
Non-polymers3141
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
6
F: DNA topoisomerase IV, B subunit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,0962
Polymers23,7821
Non-polymers3141
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
7
G: DNA topoisomerase IV, B subunit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,0962
Polymers23,7821
Non-polymers3141
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
8
H: DNA topoisomerase IV, B subunit


Theoretical massNumber of molelcules
Total (without water)23,7821
Polymers23,7821
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
9
J: DNA topoisomerase IV, B subunit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,0962
Polymers23,7821
Non-polymers3141
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
10
A: DNA topoisomerase IV, B subunit
C: DNA topoisomerase IV, B subunit
D: DNA topoisomerase IV, B subunit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,2896
Polymers71,3453
Non-polymers9433
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4980 Å2
ΔGint-20 kcal/mol
Surface area24380 Å2
MethodPISA
11
B: DNA topoisomerase IV, B subunit
hetero molecules

G: DNA topoisomerase IV, B subunit
J: DNA topoisomerase IV, B subunit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,2896
Polymers71,3453
Non-polymers9433
Water362
TypeNameSymmetry operationNumber
crystal symmetry operation3_555-x+y,-x,z+2/31
identity operation1_555x,y,z1
Buried area5080 Å2
ΔGint-16 kcal/mol
Surface area24080 Å2
MethodPISA
12
E: DNA topoisomerase IV, B subunit
hetero molecules

F: DNA topoisomerase IV, B subunit
hetero molecules

H: DNA topoisomerase IV, B subunit


Theoretical massNumber of molelcules
Total (without water)71,9745
Polymers71,3453
Non-polymers6292
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_556x,y,z+11
crystal symmetry operation3_665-x+y+1,-x+1,z+2/31
Buried area4890 Å2
ΔGint-17 kcal/mol
Surface area24690 Å2
MethodPISA
Unit cell
Length a, b, c (Å)144.210, 144.210, 84.168
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number144
Space group name H-MP31

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Components

#1: Protein
DNA topoisomerase IV, B subunit


Mass: 23781.814 Da / Num. of mol.: 9 / Fragment: unp residues 19-225
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Enterococcus faecalis (bacteria) / Strain: ATCC 700802 / V583 / Gene: parE, EF_1615 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: H7C794
#2: Chemical
ChemComp-19Y / 6-ethyl-4-methoxy-2-(pyridin-3-ylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde


Mass: 314.362 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C15H14N4O2S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 59 / 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: 2.36 Å3/Da / Density % sol: 47.9 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 20% PEG3350, 100mM Tris pH 7.5 200 mM ammonium phosphate, 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
DetectorType: NOIR-1 / Detector: CCD / Date: Feb 2, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthRelative weight: 1
ReflectionResolution: 2.7→50 Å / Num. obs: 52510 / % possible obs: 97.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0
Reflection shellResolution: 2.7→2.8 Å / % possible all: 84.1

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Processing

SoftwareName: REFMAC / Version: 5.6.0117 / Classification: refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.7→50 Å / Cor.coef. Fo:Fc: 0.912 / Cor.coef. Fo:Fc free: 0.869 / SU B: 14.798 / SU ML: 0.304 / Cross valid method: THROUGHOUT / ESU R Free: 0.403 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.2796 2663 5.1 %RANDOM
Rwork0.23117 ---
all0.33 52542 --
obs0.23361 49849 97.75 %-
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: 52.152 Å2
Baniso -1Baniso -2Baniso -3
1-2.4 Å21.2 Å20 Å2
2--2.4 Å20 Å2
3----3.61 Å2
Refinement stepCycle: LAST / Resolution: 2.7→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13272 0 176 59 13507
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.01913692
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.1381.97518473
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.00751687
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.10523.98608
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.422152376
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.7271589
X-RAY DIFFRACTIONr_chiral_restr0.0750.22060
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.02110228
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: 2.701→2.771 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.396 165 -
Rwork0.33 3073 -
obs--81.01 %

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