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- PDB-3l3r: Structural, Computational and Kinetic Data for Antifolate Interac... -

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Basic information

Entry
Database: PDB / ID: 3l3r
TitleStructural, Computational and Kinetic Data for Antifolate Interactions Against Pneumocystis jirovecii, Pneumocystis carinii and Human Dihydrofolate Reductase and Their Active Site Mutants
ComponentsDihydrofolate reductase
KeywordsOXIDOREDUCTASE / dihydrofolate reductase / antifolate / active site mutants / NADP / One-carbon metabolism
Function / homology
Function and homology information


regulation of removal of superoxide radicals / tetrahydrobiopterin biosynthetic process / Metabolism of folate and pterines / tetrahydrofolate metabolic process / sequence-specific mRNA binding / response to methotrexate / axon regeneration / folic acid binding / G1/S-Specific Transcription / dihydrofolate metabolic process ...regulation of removal of superoxide radicals / tetrahydrobiopterin biosynthetic process / Metabolism of folate and pterines / tetrahydrofolate metabolic process / sequence-specific mRNA binding / response to methotrexate / axon regeneration / folic acid binding / G1/S-Specific Transcription / dihydrofolate metabolic process / glycine biosynthetic process / dihydrofolate reductase / dihydrofolate reductase activity / folic acid metabolic process / NADPH binding / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / tetrahydrofolate biosynthetic process / mRNA regulatory element binding translation repressor activity / positive regulation of nitric-oxide synthase activity / one-carbon metabolic process / NADP binding / negative regulation of translation / mRNA binding / mitochondrion / cytosol
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-NDP / Chem-OAG / Dihydrofolate reductase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsCody, V.
CitationJournal: Antimicrob.Agents Chemother. / Year: 2013
Title: Kinetic and Structural Analysis for Potent Antifolate Inhibition of Pneumocystis jirovecii, Pneumocystis carinii, and Human Dihydrofolate Reductases and Their Active-Site Variants.
Authors: Cody, V. / Pace, J. / Queener, S.F. / Adair, O.O. / Gangjee, A.
History
DepositionDec 17, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 5, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2May 29, 2013Group: Database references
Revision 1.3Nov 1, 2017Group: Refinement description / Category: software
Revision 1.4Oct 13, 2021Group: Database references / Derived calculations / Category: 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
Revision 1.5Sep 6, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Dihydrofolate reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,5274
Polymers21,3511
Non-polymers1,1773
Water3,405189
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)84.530, 84.530, 78.423
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number146
Space group name H-MH3
Components on special symmetry positions
IDModelComponents
11A-213-

HOH

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Components

#1: Protein Dihydrofolate reductase


Mass: 21350.576 Da / Num. of mol.: 1 / Mutation: Q35K
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Plasmid: pET-SUMO / Production host: Escherichia coli (E. coli) / Strain (production host): rosetta gami B (DE3) / References: UniProt: P00374, dihydrofolate reductase
#2: Chemical ChemComp-OAG / 6-{[(2,5-dichlorophenyl)amino]methyl}pyrido[2,3-d]pyrimidine-2,4-diamine


Mass: 335.191 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H12Cl2N6
#3: Chemical ChemComp-NDP / NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE


Mass: 745.421 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H30N7O17P3
#4: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 189 / 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: 2.53 Å3/Da / Density % sol: 51.3 %
Crystal growTemperature: 280 K / Method: vapor diffusion, hanging drop / pH: 6.9
Details: 60-64% saturate ammonium sufate, 3% ethanol, pH 6.9, VAPOR DIFFUSION, HANGING DROP, temperature 280K

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Data collection

DiffractionMean temperature: 200 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU300 / Wavelength: 1.54118 Å
RadiationMonochromator: graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54118 Å / Relative weight: 1
ReflectionResolution: 2→26.1 Å / Num. all: 21070 / Num. obs: 13350 / % possible obs: 97.8 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 1 / Redundancy: 4.3 % / Biso Wilson estimate: 15 Å2 / Rmerge(I) obs: 0.18 / Rsym value: 0.1 / Net I/σ(I): 14.4
Reflection shellResolution: 2→2.1 Å / Redundancy: 4 % / Rmerge(I) obs: 0.9 / Mean I/σ(I) obs: 4.6 / Num. unique all: 2070 / Rsym value: 0.011 / % possible all: 99.9

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Processing

Software
NameVersionClassification
CrystalCleardata collection
MOLREPphasing
REFMAC5.5.0088refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1U72

1u72


Resolution: 2→26.1 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.897 / SU B: 4.154 / SU ML: 0.121 / Isotropic thermal model: isotropic / Cross valid method: THROUGHOUT / σ(I): 2 / ESU R: 0.201 / ESU R Free: 0.2 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25711 668 5 %RANDOM
Rwork0.17057 ---
all0.178 14132 --
obs0.17461 12677 94.52 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 22.161 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3----0.01 Å2
Refine analyzeLuzzati coordinate error obs: 0.19 Å
Refinement stepCycle: LAST / Resolution: 2→26.1 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1502 0 75 189 1766
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0250.0221637
X-RAY DIFFRACTIONr_angle_refined_deg2.3422.042222
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.6765189
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.36224.71470
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.55715296
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.576158
X-RAY DIFFRACTIONr_chiral_restr0.230.2235
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0211216
X-RAY DIFFRACTIONr_mcbond_it1.1831.5941
X-RAY DIFFRACTIONr_mcangle_it2.02721531
X-RAY DIFFRACTIONr_scbond_it3.3193696
X-RAY DIFFRACTIONr_scangle_it4.9564.5691
LS refinement shellResolution: 2→2.052 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.26 43 -
Rwork0.166 804 -
obs--79.23 %

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