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

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Basic information

Entry
Database: PDB / ID: 4lah
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


glycine biosynthetic process / 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 domain / Dihydrofolate reductase / Dihydrofolate reductase (DHFR) domain profile. / Dihydrofolate reductase-like domain superfamily / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-1VO / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / Dihydrofolate reductase
Similarity search - Component
Biological speciesStaphylococcus aureus (bacteria)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.88 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 1.2Nov 15, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.3Feb 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
Water1,17165
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)79.183, 79.183, 107.341
Angle α, β, γ (deg.)90.00, 90.00, 120.00
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-1VO / 7-[5,6-dimethyl-2-(1,3-thiazol-4-yl)-1H-benzimidazol-1-yl]quinazoline-2,4-diamine


Mass: 387.461 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H17N7S
#3: Chemical ChemComp-NAP / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 2'-MONOPHOSPHOADENOSINE 5'-DIPHOSPHORIBOSE / Nicotinamide adenine dinucleotide phosphate


Mass: 743.405 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H28N7O17P3
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 65 / 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: 2.51 Å3/Da / Density % sol: 51.01 %
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: 1.88 Å / Num. obs: 15303

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Phasing

PhasingMethod: molecular replacement
Phasing MRRfactor: 35.59 / Model details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation2.5 Å18.64 Å
Translation2.5 Å18.64 Å

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
PHASER2.1.1phasing
REFMACrefinement
PDB_EXTRACT3.11data extraction
DENZOdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.88→18.64 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.935 / WRfactor Rfree: 0.2411 / WRfactor Rwork: 0.1934 / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.8301 / SU B: 7.462 / SU ML: 0.115 / SU R Cruickshank DPI: 0.1534 / SU Rfree: 0.1482 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.154 / ESU R Free: 0.147 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2485 814 5.1 %RANDOM
Rwork0.2069 ---
obs0.2089 15303 96.06 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 45.27 Å2 / Biso mean: 33.705 Å2 / Biso min: 21.09 Å2
Baniso -1Baniso -2Baniso -3
1--0.12 Å2-0.06 Å20 Å2
2---0.12 Å20 Å2
3---0.18 Å2
Refinement stepCycle: LAST / Resolution: 1.88→18.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1272 0 76 65 1413
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0221390
X-RAY DIFFRACTIONr_angle_refined_deg1.5932.0211900
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7995156
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.37424.19462
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.98715226
X-RAY DIFFRACTIONr_dihedral_angle_4_deg9.725156
X-RAY DIFFRACTIONr_chiral_restr0.0730.2207
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.021041
X-RAY DIFFRACTIONr_nbd_refined0.1720.2605
X-RAY DIFFRACTIONr_nbtor_refined0.3030.2926
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1120.292
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2160.233
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.4320.214
X-RAY DIFFRACTIONr_mcbond_it0.3541.5806
X-RAY DIFFRACTIONr_mcangle_it0.58221282
X-RAY DIFFRACTIONr_scbond_it0.9913703
X-RAY DIFFRACTIONr_scangle_it1.4794.5618
LS refinement shellResolution: 1.879→1.927 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.483 42 -
Rwork0.504 696 -
all-738 -
obs--62.17 %
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)
12.10141.02770.67651.9768-1.51634.34730.0342-0.0303-0.06910.16990.03230.0283-0.4771-0.1364-0.0665-0.0397-0.01660.1189-0.1545-0.0245-0.1186-1.32624.538-8.644
21.50321.69130.74812.6152-0.4622.75850.188-0.08620.31750.2895-0.08520.4182-0.7805-0.1417-0.10280.17640.0210.2053-0.1257-0.052-0.0021-5.72933.846-3.114
34.95333.2838-1.05515.8366-2.92433.77740.5793-0.47210.13711.148-0.5379-0.1941-0.39430.2745-0.04140.3278-0.21240.0601-0.0926-0.0682-0.10887.63937.4954.462
41.70220.9352-0.23821.6644-0.07942.41550.1942-0.1478-0.07780.1937-0.0656-0.1805-0.45780.0568-0.12860.0037-0.04990.0913-0.1439-0.0124-0.10470.23523.901-3.081
57.6644-0.9385-5.329113.2992-5.69919.9219-0.467-0.2664-0.96830.02750.0572-0.43310.83260.02950.40980.042-0.02040.0904-0.13430.0349-0.0190.85113.132-4.179
65.155-0.36973.08752.6063-2.56238.61770.0465-0.02160.12390.03090.01170.0428-0.2534-0.3305-0.0582-0.07320.01960.0861-0.15590.0307-0.1396-11.81118.557-3.728
71.4847-0.4731.62092.867-0.17332.25410.07710.12720.01650.146-0.1279-0.1184-0.33970.3240.05070.1142-0.12320.1497-0.0846-0.0245-0.02796.82631.52-6.093
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 - 202

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