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- PDB-4kd7: Human dihydrofolate reductase complexed with NADPH and 5-{3-[3-me... -

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Basic information

Entry
Database: PDB / ID: 4kd7
TitleHuman dihydrofolate reductase complexed with NADPH and 5-{3-[3-methoxy-5(pyridine-4-yl)phenyl]prop-1-yn-1-yl}-6-ethyl-pyrimidine-2,4-diamine
ComponentsDihydrofolate reductase
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / Oxidoreductase / 5 / 6 / 7 / 8-tetrahydrofolate / NADP+ / hydride shift / cytosol / 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 / response to methotrexate / sequence-specific mRNA binding / axon regeneration / folic acid binding / 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 / axon regeneration / folic acid binding / 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 / positive regulation of nitric-oxide synthase activity / 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-9DR / Chem-NDP / Dihydrofolate reductase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.715 Å
AuthorsLamb, K.M. / Anderson, A.C.
CitationJournal: Biochemistry / Year: 2013
Title: Elucidating features that drive the design of selective antifolates using crystal structures of human dihydrofolate reductase.
Authors: Lamb, K.M. / G-Dayanandan, N. / Wright, D.L. / Anderson, A.C.
History
DepositionApr 24, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 9, 2013Provider: repository / Type: Initial release
Revision 1.1Oct 30, 2013Group: Database references
Revision 1.2Nov 20, 2013Group: Non-polymer description
Revision 1.3Dec 17, 2014Group: Data collection
Revision 1.4Sep 20, 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
B: Dihydrofolate reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,29310
Polymers42,6992
Non-polymers2,5948
Water2,450136
1
A: Dihydrofolate reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,6465
Polymers21,3501
Non-polymers1,2974
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Dihydrofolate reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,6465
Polymers21,3501
Non-polymers1,2974
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)105.258, 105.249, 144.684
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-323-

HOH

21B-320-

HOH

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Components

#1: Protein Dihydrofolate reductase


Mass: 21349.525 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DHFR, huDHFR / Plasmid: pET41a(+) / 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


Mass: 745.421 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H30N7O17P3
#3: Chemical ChemComp-9DR / 6-ethyl-5-{3-[3-methoxy-5-(pyridin-4-yl)phenyl]prop-1-yn-1-yl}pyrimidine-2,4-diamine


Mass: 359.424 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H21N5O
#4: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 136 / 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: 4.69 Å3/Da / Density % sol: 73.79 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 0.1M Tris-HCl, 0.2-0.3M Lithium sulfate, 25-32%(w/v) PEG 4000, pH 7.5, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X4A / Wavelength: 0.97916 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Jun 29, 2012
RadiationMonochromator: ADSC Quantum 4R / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97916 Å / Relative weight: 1
ReflectionResolution: 2.715→33.28 Å / Num. all: 22044 / Num. obs: 21954 / % possible obs: 99.59 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0
Reflection shellResolution: 2.715→2.76 Å / % possible all: 99.3

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Processing

Software
NameVersionClassification
HKL-2000data collection
PHASERphasing
PHENIX(phenix.refine: 1.8_1069)refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2W3A

2w3a


Resolution: 2.715→33.28 Å / SU ML: 0.24 / σ(F): 1.35 / Phase error: 22.13 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2197 1122 5.12 %
Rwork0.1743 --
obs0.1766 21899 99.39 %
all-22044 -
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.715→33.28 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3002 0 170 136 3308
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0053338
X-RAY DIFFRACTIONf_angle_d0.9014544
X-RAY DIFFRACTIONf_dihedral_angle_d14.9911292
X-RAY DIFFRACTIONf_chiral_restr0.066469
X-RAY DIFFRACTIONf_plane_restr0.003576
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.7153-2.83880.30051330.21072518X-RAY DIFFRACTION98
2.8388-2.98840.27341490.20492563X-RAY DIFFRACTION100
2.9884-3.17550.27421320.19812561X-RAY DIFFRACTION100
3.1755-3.42050.23671230.18472611X-RAY DIFFRACTION100
3.4205-3.76420.22841480.15282610X-RAY DIFFRACTION100
3.7642-4.3080.18091540.14922572X-RAY DIFFRACTION100
4.308-5.42380.1881440.14672652X-RAY DIFFRACTION100
5.4238-33.28770.20731390.2052690X-RAY DIFFRACTION98

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