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

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Basic information

Entry
Database: PDB / ID: 4keb
TitleHuman dihydrofolate reductase complexed with NADPH and 5-{3-[3-methoxy-5-(isoquin-5-yl)phenyl]but-1-yn-1-yl}6-ethylpyrimidine-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-1QZ / FOLIC ACID / Chem-NDP / Dihydrofolate reductase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.45 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 25, 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)45,0556
Polymers42,6992
Non-polymers2,3564
Water7,692427
1
A: Dihydrofolate reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,5183
Polymers21,3501
Non-polymers1,1692
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Dihydrofolate reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,5363
Polymers21,3501
Non-polymers1,1872
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)87.709, 93.659, 96.155
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-347-

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-1QZ / 6-ethyl-5-{(3S)-3-[3-(isoquinolin-5-yl)-5-methoxyphenyl]but-1-yn-1-yl}pyrimidine-2,4-diamine


Mass: 423.510 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H25N5O
#4: Chemical ChemComp-FOL / FOLIC ACID


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


Mass: 18.015 Da / Num. of mol.: 427 / 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: 2.31 Å3/Da / Density % sol: 46.81 %
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: 0.97016 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Jun 12, 2012
RadiationMonochromator: ADSC Quantum 4R / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97016 Å / Relative weight: 1
ReflectionResolution: 1.45→50 Å / Num. all: 92682 / Num. obs: 92033 / % possible obs: 99.3 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 8 %
Reflection shellResolution: 1.45→1.49 Å / % possible all: 100

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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: 2C2S

2c2s


Resolution: 1.45→16.096 Å / SU ML: 0.13 / σ(F): 1.35 / Phase error: 19.62 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2062 3471 4.98 %Random
Rwork0.1674 ---
all0.1693 70179 --
obs0.1693 69735 99.37 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.45→16.096 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3004 0 160 427 3591
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0123480
X-RAY DIFFRACTIONf_angle_d1.5894749
X-RAY DIFFRACTIONf_dihedral_angle_d14.6931374
X-RAY DIFFRACTIONf_chiral_restr0.099501
X-RAY DIFFRACTIONf_plane_restr0.008602
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.45-1.46980.19981340.1792638X-RAY DIFFRACTION100
1.4698-1.49080.21791530.18422643X-RAY DIFFRACTION100
1.4908-1.5130.26211420.17872640X-RAY DIFFRACTION100
1.513-1.53670.25741310.17442624X-RAY DIFFRACTION100
1.5367-1.56180.24031640.16992635X-RAY DIFFRACTION100
1.5618-1.58880.25971360.15622608X-RAY DIFFRACTION100
1.5888-1.61760.21971330.14952661X-RAY DIFFRACTION100
1.6176-1.64870.23171420.14952651X-RAY DIFFRACTION100
1.6487-1.68230.2211380.15942618X-RAY DIFFRACTION100
1.6823-1.71890.21871410.1572631X-RAY DIFFRACTION100
1.7189-1.75880.19911350.15522647X-RAY DIFFRACTION100
1.7588-1.80270.19871220.15332657X-RAY DIFFRACTION99
1.8027-1.85140.22221390.15942627X-RAY DIFFRACTION99
1.8514-1.90580.21351420.16032631X-RAY DIFFRACTION99
1.9058-1.96720.21011260.15682647X-RAY DIFFRACTION99
1.9672-2.03740.20691340.15232660X-RAY DIFFRACTION100
2.0374-2.11880.2021470.15322640X-RAY DIFFRACTION100
2.1188-2.2150.21871360.15532676X-RAY DIFFRACTION100
2.215-2.33140.18831560.16632622X-RAY DIFFRACTION99
2.3314-2.4770.20571350.16992678X-RAY DIFFRACTION99
2.477-2.66750.24751370.17712672X-RAY DIFFRACTION99
2.6675-2.93450.21661280.19052680X-RAY DIFFRACTION99
2.9345-3.35570.20051220.1792725X-RAY DIFFRACTION100
3.3557-4.21530.18511280.15382679X-RAY DIFFRACTION98
4.2153-16.09670.19091700.17982674X-RAY DIFFRACTION96

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