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

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Basic information

Entry
Database: PDB / ID: 4hyp
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 / Gyrase / GyrB / ATP-binding / Nucleotide-binding / Topoisomerase / ATP-binding domain / Isomerase-Isomerase inhibitor complex
Function / homology
Function and homology information


DNA negative supercoiling activity / DNA topoisomerase type II (double strand cut, ATP-hydrolyzing) complex / DNA topoisomerase type II (double strand cut, ATP-hydrolyzing) activity / DNA topoisomerase (ATP-hydrolysing) / DNA topological change / ATP-dependent activity, acting on DNA / DNA-templated DNA replication / chromosome / response to xenobiotic stimulus / response to antibiotic ...DNA negative supercoiling activity / DNA topoisomerase type II (double strand cut, ATP-hydrolyzing) complex / DNA topoisomerase type II (double strand cut, ATP-hydrolyzing) activity / DNA topoisomerase (ATP-hydrolysing) / DNA topological change / ATP-dependent activity, acting on DNA / DNA-templated DNA replication / chromosome / response to xenobiotic stimulus / response to antibiotic / DNA-templated transcription / DNA binding / ATP binding / metal ion binding / cytosol / cytoplasm
Similarity search - Function
: / GyrB, hook / DNA gyrase subunit B insert domain / DNA gyrase B subunit insert domain / 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 ...: / GyrB, hook / DNA gyrase subunit B insert domain / DNA gyrase B subunit insert domain / 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 / 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-1A1 / DNA gyrase subunit B
Similarity search - Component
Biological speciesEscherichia coli (E. coli)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 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 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 / pdbx_struct_conn_angle / struct_conn / 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 / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _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

Downloads & links

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Assembly

Deposited unit
A: DNA gyrase subunit B
B: DNA gyrase subunit B
C: DNA gyrase subunit B
D: DNA gyrase subunit B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)96,95412
Polymers95,4034
Non-polymers1,5518
Water6,756375
1
A: DNA gyrase subunit B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,2383
Polymers23,8511
Non-polymers3882
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: DNA gyrase subunit B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,2383
Polymers23,8511
Non-polymers3882
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: DNA gyrase subunit B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,2383
Polymers23,8511
Non-polymers3882
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: DNA gyrase subunit B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,2383
Polymers23,8511
Non-polymers3882
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
5
A: DNA gyrase subunit B
B: DNA gyrase subunit B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)48,4776
Polymers47,7022
Non-polymers7754
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2210 Å2
ΔGint-28 kcal/mol
Surface area16780 Å2
MethodPISA
6
C: DNA gyrase subunit B
D: DNA gyrase subunit B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)48,4776
Polymers47,7022
Non-polymers7754
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2200 Å2
ΔGint-27 kcal/mol
Surface area16760 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.408, 101.312, 82.282
Angle α, β, γ (deg.)90.00, 101.60, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein
DNA gyrase subunit B /


Mass: 23850.771 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Escherichia coli (E. coli) / Strain: K12 / Gene: acrB, b3699, gyrB, himB, hisU, JW5625, nalC / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P0AES6, EC: 5.99.1.3
#2: Chemical
ChemComp-1A1 / N-[7-(1H-imidazol-1-yl)-2-(pyridin-3-yl)[1,3]thiazolo[5,4-d]pyrimidin-5-yl]cyclopropanecarboxamide


Mass: 363.396 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C17H13N7OS
#3: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Mg
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 375 / 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: 2.07 Å3/Da / Density % sol: 40.63 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 30% PEG4000, 200 mM MgCl2, 100 mM Tris , pH 8.0, VAPOR DIFFUSION, SITTING 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: Jun 19, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthRelative weight: 1
ReflectionResolution: 2.6→42.89 Å / Num. all: 93667 / Num. obs: 23154 / % possible obs: 96.4 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0
Reflection shellResolution: 2.6→2.69 Å / % possible all: 96.8

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Processing

SoftwareName: REFMAC / Version: 5.6.0117 / Classification: refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.6→42.89 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.879 / SU B: 14.361 / SU ML: 0.304 / Cross valid method: THROUGHOUT / ESU R Free: 0.428 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.29406 1188 5.1 %RANDOM
Rwork0.19515 ---
all0.255 93667 --
obs0.20039 21938 96.3 %-
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: 30.665 Å2
Baniso -1Baniso -2Baniso -3
1-0.34 Å20 Å20.73 Å2
2---0.67 Å20 Å2
3---0.62 Å2
Refinement stepCycle: LAST / Resolution: 2.6→42.89 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5992 0 108 375 6475
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0196212
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.8041.9688388
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.8765764
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.34723.714280
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.649151056
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.8641544
X-RAY DIFFRACTIONr_chiral_restr0.1150.2940
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0214668
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: 2.6→2.668 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.36 82 -
Rwork0.255 1619 -
obs--97.48 %

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