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- PDB-4ddr: Human dihydrofolate reductase complexed with NADPH and P218 -

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Basic information

Entry
Database: PDB / ID: 4ddr
TitleHuman dihydrofolate reductase complexed with NADPH and P218
ComponentsDihydrofolate reductase
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / antifolate / NADPH / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBITOR complex
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 / dihydrofolate metabolic process / axon regeneration / folic acid binding / G1/S-Specific Transcription ...regulation of removal of superoxide radicals / tetrahydrobiopterin biosynthetic process / Metabolism of folate and pterines / tetrahydrofolate metabolic process / sequence-specific mRNA binding / response to methotrexate / dihydrofolate metabolic process / axon regeneration / folic acid binding / G1/S-Specific Transcription / folic acid metabolic process / glycine biosynthetic process / dihydrofolate reductase / dihydrofolate reductase activity / 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-MMV / Chem-NDP / Dihydrofolate reductase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.05 Å
AuthorsYuthavong, Y. / Tarnchompoo, B. / Vilaivan, T. / Chitnumsub, P. / Kamchonwongpaisan, S. / Charman, S.A. / McLennan, D.N. / White, K.L. / Vivas, L. / Bongard, E. ...Yuthavong, Y. / Tarnchompoo, B. / Vilaivan, T. / Chitnumsub, P. / Kamchonwongpaisan, S. / Charman, S.A. / McLennan, D.N. / White, K.L. / Vivas, L. / Bongard, E. / Thongphanchang, C. / Taweechai, S. / Vanichtanankul, J. / Rattanajak, R. / Arwon, U. / Fantauzzi, P. / Yuvaniyama, J. / Charman, W.N. / Matthews, D.
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2012
Title: Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target
Authors: Yuthavong, Y. / Tarnchompoo, B. / Vilaivan, T. / Chitnumsub, P. / Kamchonwongpaisan, S. / Charman, S.A. / McLennan, D.N. / White, K.L. / Vivas, L. / Bongard, E. / Thongphanchang, C. / ...Authors: Yuthavong, Y. / Tarnchompoo, B. / Vilaivan, T. / Chitnumsub, P. / Kamchonwongpaisan, S. / Charman, S.A. / McLennan, D.N. / White, K.L. / Vivas, L. / Bongard, E. / Thongphanchang, C. / Taweechai, S. / Vanichtanankul, J. / Rattanajak, R. / Arwon, U. / Fantauzzi, P. / Yuvaniyama, J. / Charman, W.N. / Matthews, D.
History
DepositionJan 19, 2012Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Nov 14, 2012Provider: repository / Type: Initial release
Revision 1.1Nov 8, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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: Dihydrofolate reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,4553
Polymers21,3501
Non-polymers1,1062
Water3,099172
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)85.285, 85.285, 77.131
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number146
Space group name H-MH3

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Components

#1: Protein Dihydrofolate reductase /


Mass: 21349.525 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DHFR / Plasmid: pET17b / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P00374, dihydrofolate reductase
#2: Chemical ChemComp-NDP / NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / Nicotinamide adenine dinucleotide phosphate


Mass: 745.421 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H30N7O17P3
#3: Chemical ChemComp-MMV / 3-(2-{3-[(2,4-diamino-6-ethylpyrimidin-5-yl)oxy]propoxy}phenyl)propanoic acid


Mass: 360.408 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H24N4O4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 172 / 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: 51.36 % / Mosaicity: 0.67 °
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop
Details: 2.78M Ammonium sulphate, 100mM K2HPO4, 3%(v/v) Ethanol, VAPOR DIFFUSION, HANGING DROP, temperature 295K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RUH3R / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Oct 1, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.05→33.31 Å / Num. obs: 13123 / % possible obs: 95.1 % / Redundancy: 1.64 % / Rmerge(I) obs: 0.07 / Χ2: 1 / Net I/σ(I): 5.2 / Scaling rejects: 312
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allΧ2% possible allRejects
2.05-2.121.640.2441.8401824540.7393.2
2.12-2.211.650.2052.2405624630.7193.6
2.21-2.311.650.1732.7405524640.8193.8
2.31-2.431.660.1393.2406324450.7593.7
2.43-2.581.660.1213.9408124630.8694.4
2.58-2.781.660.1094.5415824960.9694.93
2.78-3.061.660.0885.8418125221.1495.22
3.06-3.51.650.0657.7415325141.3596.516
3.5-4.411.620.0519.5425825871.597.967
4.41-33.311.580.04910.1426125611.2497.5224

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
d*TREK7.1SSIdata scaling
d*TREK7.1SSIdata reduction
MOLREPphasing
CNS1.2refinement
PDB_EXTRACT3.1data extraction
CrystalCleardata collection
CrystalCleardata reduction
CrystalCleardata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1HFR

1hfr


Resolution: 2.05→33.31 Å / Rfactor Rfree error: 0.01 / Occupancy max: 1 / Occupancy min: 1 / Data cutoff high absF: 274879 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Details: BULK SOLVENT MODEL USED
RfactorNum. reflection% reflectionSelection details
Rfree0.249 655 5 %RANDOM
Rwork0.205 ---
obs-13122 99.8 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 69.3711 Å2 / ksol: 0.4 e/Å3
Displacement parametersBiso max: 73.7 Å2 / Biso mean: 32.2186 Å2 / Biso min: 15.6 Å2
Baniso -1Baniso -2Baniso -3
1-2.35 Å20 Å20 Å2
2--2.35 Å20 Å2
3----4.7 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.32 Å0.25 Å
Luzzati d res low-5 Å
Luzzati sigma a0.3 Å0.22 Å
Refinement stepCycle: LAST / Resolution: 2.05→33.31 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1502 0 74 172 1748
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.007
X-RAY DIFFRACTIONc_angle_deg1.4
X-RAY DIFFRACTIONc_dihedral_angle_d23.6
X-RAY DIFFRACTIONc_improper_angle_d0.88
X-RAY DIFFRACTIONc_mcbond_it1.381.5
X-RAY DIFFRACTIONc_mcangle_it2.172
X-RAY DIFFRACTIONc_scbond_it1.962
X-RAY DIFFRACTIONc_scangle_it2.82.5
LS refinement shellResolution: 2.05→2.12 Å / Rfactor Rfree error: 0.055 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.424 59 4.5 %
Rwork0.307 1257 -
all-1316 -
obs--100 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paramprotein.top
X-RAY DIFFRACTION2water.paramligands.top
X-RAY DIFFRACTION3ligands.paramwater.top

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