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- PDB-4lae: Structure-Based Design of New Dihydrofolate Reductase Antibacteri... -

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Basic information

Entry
Database: PDB / ID: 4lae
TitleStructure-Based Design of New Dihydrofolate Reductase Antibacterial Agents: 7-(Benzimidazol-1-yl)-2,4-diaminoquinazolines
ComponentsDihydrofolate reductase
KeywordsOxidoreductase/Oxidoreductase inhibitor / DHFR / protein-inhibitor complex / folate / NADPH / Oxidoreductase-Oxidoreductase inhibitor complex
Function / homology
Function and homology information


dihydrofolate reductase / dihydrofolate reductase activity / tetrahydrofolate biosynthetic process / one-carbon metabolic process / NADP binding
Similarity search - Function
Dihydrofolate Reductase, subunit A / Dihydrofolate Reductase, subunit A / Dihydrofolate reductase / Dihydrofolate reductase conserved site / Dihydrofolate reductase (DHFR) domain signature. / Dihydrofolate reductase (DHFR) domain profile. / Dihydrofolate reductase domain / Dihydrofolate reductase / Dihydrofolate reductase-like domain superfamily / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-1VM / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / Dihydrofolate reductase
Similarity search - Component
Biological speciesStaphylococcus aureus (bacteria)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.69 Å
AuthorsHilgers, M.T.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Structure-Based Design of New Dihydrofolate Reductase Antibacterial Agents: 7-(Benzimidazol-1-yl)-2,4-diaminoquinazolines.
Authors: Lam, T. / Hilgers, M.T. / Cunningham, M.L. / Kwan, B.P. / Nelson, K.J. / Brown-Driver, V. / Ong, V. / Trzoss, M. / Hough, G. / Shaw, K.J. / Finn, J.
History
DepositionJun 19, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 19, 2014Provider: repository / Type: Initial release
Revision 1.1Feb 26, 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_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

Downloads & links

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Assembly

Deposited unit
X: Dihydrofolate reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,4783
Polymers19,3471
Non-polymers1,1312
Water2,126118
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)79.360, 79.360, 107.104
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number178
Space group name H-MP6122

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Components

#1: Protein Dihydrofolate reductase / DHFR


Mass: 19347.088 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Staphylococcus aureus (bacteria) / Gene: folA / Plasmid: pET28 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21-AI / References: UniProt: P0A017, dihydrofolate reductase
#2: Chemical ChemComp-NAP / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 2'-MONOPHOSPHOADENOSINE 5'-DIPHOSPHORIBOSE


Mass: 743.405 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H28N7O17P3
#3: Chemical ChemComp-1VM / 7-[5,6-dimethyl-2-(1,3-thiazol-2-yl)-1H-benzimidazol-1-yl]quinazoline-2,4-diamine


Mass: 387.461 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H17N7S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 118 / 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: 2.52 Å3/Da / Density % sol: 51.12 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.2
Details: PEG 4000, sodium acetate, pH 7.2, vapor diffusion, hanging drop, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU / Wavelength: 1.5418 Å
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionHighest resolution: 1.69 Å / Num. obs: 21614

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Phasing

PhasingMethod: molecular replacement
Phasing MRRfactor: 32.66 / Model details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation2.5 Å18.85 Å
Translation2.5 Å18.85 Å

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Processing

Software
NameVersionClassificationNB
MOSFLMdata reduction
SCALEPACKdata scaling
PHASER2.1.1phasing
REFMACrefinement
PDB_EXTRACT3.11data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.69→18.85 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.943 / WRfactor Rfree: 0.2314 / WRfactor Rwork: 0.1995 / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.8648 / SU B: 3.606 / SU ML: 0.063 / SU R Cruickshank DPI: 0.1031 / SU Rfree: 0.1029 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.102 / ESU R Free: 0.101 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2245 1175 5.2 %RANDOM
Rwork0.1938 ---
obs0.1953 21614 98.56 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 43.79 Å2 / Biso mean: 23.59 Å2 / Biso min: 12.95 Å2
Baniso -1Baniso -2Baniso -3
1--0.15 Å2-0.07 Å20 Å2
2---0.15 Å20 Å2
3---0.22 Å2
Refinement stepCycle: LAST / Resolution: 1.69→18.85 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1272 0 76 118 1466
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0221390
X-RAY DIFFRACTIONr_angle_refined_deg1.6522.0211900
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9985156
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.92824.19462
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.3615226
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.213156
X-RAY DIFFRACTIONr_chiral_restr0.0740.2207
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.021041
X-RAY DIFFRACTIONr_nbd_refined0.1830.2599
X-RAY DIFFRACTIONr_nbtor_refined0.3060.2936
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.0840.2130
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2060.237
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1410.217
X-RAY DIFFRACTIONr_mcbond_it0.4291.5803
X-RAY DIFFRACTIONr_mcangle_it0.70121282
X-RAY DIFFRACTIONr_scbond_it1.13705
X-RAY DIFFRACTIONr_scangle_it1.7244.5618
LS refinement shellResolution: 1.685→1.729 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.527 79 -
Rwork0.434 1305 -
all-1384 -
obs--83.22 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.57770.56480.28921.8922-0.13942.19290.0344-0.0235-0.06640.1231-0.0174-0.0218-0.2244-0.0361-0.017-0.0013-0.01490.0583-0.0676-0.0087-0.0912-1.28524.57-8.622
21.09491.17220.20181.7759-0.30541.10370.1301-0.09180.21770.2513-0.04980.3259-0.396-0.0758-0.08040.12350.01510.119-0.0604-0.0253-0.0176-5.73933.907-3.186
34.24843.0692-1.42414.4943-1.64371.60040.4096-0.3530.20411.021-0.3974-0.0746-0.19270.1364-0.01220.2406-0.12620.0364-0.0425-0.0326-0.12357.57937.6544.43
41.60710.9523-0.3561.43180.00892.03170.1266-0.1436-0.10960.2234-0.0507-0.0975-0.2180.03-0.07590.0192-0.01940.0379-0.0720.0026-0.08890.2523.979-3.047
58.0445-1.2649-2.081115.6356-6.72989.7667-0.3354-0.2342-0.8690.08480.2054-0.15950.7509-0.06130.130.0643-0.00250.0521-0.06250.0212-0.04080.89913.203-4.06
64.0019-0.45692.64693.16-3.21467.8025-0.0127-0.00590.05210.03630.09340.0154-0.1572-0.2745-0.0807-0.04780.010.0534-0.08210.0207-0.1251-11.77818.593-3.715
70.52350.8162-1.00063.315-0.77542.21420.0414-0.08140.0220.1792-0.1057-0.0653-0.17780.1490.06430.0813-0.06370.0448-0.0433-0.0124-0.0546.83531.597-6.083
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1X2 - 20
2X-RAY DIFFRACTION2X21 - 57
3X-RAY DIFFRACTION3X58 - 85
4X-RAY DIFFRACTION4X86 - 123
5X-RAY DIFFRACTION5X124 - 130
6X-RAY DIFFRACTION6X131 - 158
7X-RAY DIFFRACTION7X201

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