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

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Basic information

Entry
Database: PDB / ID: 4kfj
TitleHuman dihydrofolate reductase complexed with NADPH and 5-{3-[3-methoxy-5-(isoquin-5-yl)phenyl]prop-1-yn-1-yl}6-ethylprimidine-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 / 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-1R0 / ETHANOL / FOLIC ACID / Chem-NDP / Dihydrofolate reductase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.76 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 26, 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 / pdbx_struct_conn_angle / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _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)45,27914
Polymers42,6992
Non-polymers2,58012
Water6,954386
1
A: Dihydrofolate reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,6357
Polymers21,3501
Non-polymers1,2856
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Dihydrofolate reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,6457
Polymers21,3501
Non-polymers1,2956
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)87.811, 94.075, 96.294
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-326-

HOH

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Components

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Protein , 1 types, 2 molecules AB

#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

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Non-polymers , 7 types, 398 molecules

#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-1R0 / 6-ethyl-5-{3-[3-(isoquinolin-5-yl)-5-methoxyphenyl]prop-1-yn-1-yl}pyrimidine-2,4-diamine


Mass: 409.483 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H23N5O
#4: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Mg
#5: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#6: Chemical ChemComp-EOH / ETHANOL


Mass: 46.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O
#7: Chemical ChemComp-FOL / FOLIC ACID


Mass: 441.397 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H19N7O6
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 386 / 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: 2.33 Å3/Da / Density % sol: 47.18 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 0.1M Tris-HCl, 0.2-0.3M Lithium sulfate, 25-30% (w/v) PEG 4000, 1% (v/v) trifluoroethanol, 11mM MgCl2, 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: 1.76→50 Å / Num. obs: 39426 / % possible obs: 98.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0
Reflection shellResolution: 1.76→1.79 Å / % possible all: 97

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Processing

Software
NameVersionClassification
HKL-2000data collection
PHASERfor MRphasing
PHENIX(phenix.refine: 1.8_1069)refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2C2S

2c2s


Resolution: 1.76→19.893 Å / SU ML: 0.23 / σ(F): 1.35 / Phase error: 25.36 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2451 1970 5.01 %Random
Rwork0.1962 ---
all0.1986 39827 --
obs0.1986 39299 98.67 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.76→19.893 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3004 0 169 386 3559
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0123409
X-RAY DIFFRACTIONf_angle_d1.64652
X-RAY DIFFRACTIONf_dihedral_angle_d17.1021360
X-RAY DIFFRACTIONf_chiral_restr0.103490
X-RAY DIFFRACTIONf_plane_restr0.007586
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.76-1.80350.34651490.26782613X-RAY DIFFRACTION99
1.8035-1.85220.31691690.2422632X-RAY DIFFRACTION100
1.8522-1.90670.28861290.22952669X-RAY DIFFRACTION99
1.9067-1.96810.2821330.23172683X-RAY DIFFRACTION100
1.9681-2.03840.29251410.2232660X-RAY DIFFRACTION100
2.0384-2.120.24151130.21372700X-RAY DIFFRACTION100
2.12-2.21630.27391500.21112677X-RAY DIFFRACTION100
2.2163-2.3330.27681300.21672685X-RAY DIFFRACTION100
2.333-2.47890.29911550.21832690X-RAY DIFFRACTION100
2.4789-2.66990.25231630.2172664X-RAY DIFFRACTION100
2.6699-2.93780.25531480.20932695X-RAY DIFFRACTION100
2.9378-3.36120.22631350.18572712X-RAY DIFFRACTION99
3.3612-4.2280.22651260.15512659X-RAY DIFFRACTION96
4.228-19.89420.17381290.17092590X-RAY DIFFRACTION91

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