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- PDB-6a7e: Human dihydrofolate reductase complexed with NADPH and BT2 -

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Basic information

Entry
Database: PDB / ID: 6a7e
TitleHuman dihydrofolate reductase complexed with NADPH and BT2
ComponentsDihydrofolate reductase
KeywordsOXIDOREDUCTASE / DHFR / antifolate / inhibitor
Function / homology
Function and homology information


regulation of removal of superoxide radicals / tetrahydrobiopterin biosynthetic process / Metabolism of folate and pterines / tetrahydrofolate metabolic process / response to methotrexate / sequence-specific mRNA binding / folic acid binding / axon regeneration / dihydrofolate metabolic process / G1/S-Specific Transcription ...regulation of removal of superoxide radicals / tetrahydrobiopterin biosynthetic process / Metabolism of folate and pterines / tetrahydrofolate metabolic process / response to methotrexate / sequence-specific mRNA binding / folic acid binding / axon regeneration / dihydrofolate metabolic process / G1/S-Specific Transcription / dihydrofolate reductase / dihydrofolate reductase activity / folic acid metabolic process / NADPH binding / tetrahydrofolate biosynthetic process / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / one-carbon metabolic process / mRNA regulatory element binding translation repressor activity / NADP binding / negative regulation of translation / mRNA binding / mitochondrion / cytosol
Similarity search - Function
Dihydrofolate reductase / Dihydrofolate Reductase, subunit A / Dihydrofolate Reductase, subunit A / 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-9QR / Chem-NDP / Dihydrofolate reductase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.85 Å
AuthorsVanichtanankul, J. / Tarnchompoo, B. / Chitnumsub, P. / Kamchonwongpaisan, S. / Yuthavong, Y.
Funding support United States, 1items
OrganizationGrant numberCountry
Bill & Melinda Gates Foundation52992 United States
CitationJournal: ACS Med Chem Lett / Year: 2018
Title: Hybrid Inhibitors of Malarial Dihydrofolate Reductase with Dual Binding Modes That Can Forestall Resistance.
Authors: Tarnchompoo, B. / Chitnumsub, P. / Jaruwat, A. / Shaw, P.J. / Vanichtanankul, J. / Poen, S. / Rattanajak, R. / Wongsombat, C. / Tonsomboon, A. / Decharuangsilp, S. / Anukunwithaya, T. / ...Authors: Tarnchompoo, B. / Chitnumsub, P. / Jaruwat, A. / Shaw, P.J. / Vanichtanankul, J. / Poen, S. / Rattanajak, R. / Wongsombat, C. / Tonsomboon, A. / Decharuangsilp, S. / Anukunwithaya, T. / Arwon, U. / Kamchonwongpaisan, S. / Yuthavong, Y.
History
DepositionJul 2, 2018Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 10, 2019Provider: repository / Type: Initial release
Revision 1.1Nov 22, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)22,5193
Polymers21,3501
Non-polymers1,1702
Water2,900161
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1180 Å2
ΔGint-5 kcal/mol
Surface area9600 Å2
MethodPISA
Unit cell
Length a, b, c (Å)84.755, 84.755, 77.726
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 BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: P00374, dihydrofolate reductase
#2: Chemical ChemComp-9QR / 5-(4-{3-[(2,4-diamino-6-ethylpyrimidin-5-yl)oxy]propoxy}phenyl)-6-ethylpyrimidine-2,4-diamine


Mass: 424.499 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H28N8O2 / Feature type: SUBJECT OF INVESTIGATION
#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: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 161 / 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: 297 K / Method: vapor diffusion, hanging drop
Details: 2.78 M AMMONIUM SULPHATE, 100 mM K2HPO4, 3%(V/V) ETHANOL

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: ENRAF-NONIUS FR591 / Wavelength: 1.5418 Å
DetectorType: Nonius Kappa CCD / Detector: CCD / Date: Jul 15, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.85→50 Å / Num. obs: 17677 / % possible obs: 99.3 % / Redundancy: 2.5 % / Rmerge(I) obs: 0.047 / Χ2: 1.058 / Net I/σ(I): 20.2
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
1.85-1.922.50.25817921.091199.7
1.92-1.992.50.19217441.106199.9
1.99-2.082.50.13317881.082199.9
2.08-2.192.50.117751.0981100
2.19-2.332.50.0817661.063199.8
2.33-2.512.60.06617901.02199.9
2.51-2.762.60.05317821.042199.9
2.76-3.162.60.04217741.006199.8
3.16-3.992.60.03217771.017199.4
3.99-502.60.02916891.068195

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Processing

Software
NameVersionClassification
HKL-2000data scaling
REFMAC5.7.0032refinement
PDB_EXTRACT3.24data extraction
DENZOdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4DDR

4ddr


Resolution: 1.85→42.41 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.918 / SU B: 2.978 / SU ML: 0.092 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.151 / ESU R Free: 0.144
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2375 882 5 %RANDOM
Rwork0.1897 ---
obs0.1919 16795 99.28 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 70.21 Å2 / Biso mean: 22.622 Å2 / Biso min: 9.69 Å2
Baniso -1Baniso -2Baniso -3
1-0.09 Å20.09 Å20 Å2
2--0.09 Å20 Å2
3----0.3 Å2
Refinement stepCycle: final / Resolution: 1.85→42.41 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1502 0 79 161 1742
Biso mean--17.88 28.11 -
Num. residues----186
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.021622
X-RAY DIFFRACTIONr_bond_other_d0.0040.021539
X-RAY DIFFRACTIONr_angle_refined_deg1.5332.0382200
X-RAY DIFFRACTIONr_angle_other_deg13.0183557
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0795185
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.56724.78971
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.59215286
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.928158
X-RAY DIFFRACTIONr_chiral_restr0.0920.2233
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0211771
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02359
LS refinement shellResolution: 1.849→1.897 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.295 54 -
Rwork0.265 1238 -
all-1292 -
obs--99.46 %

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