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- PDB-4kbn: human dihydrofolate reductase complexed with NADPH and 5-{3-[3-(3... -

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Basic information

Entry
Database: PDB / ID: 4kbn
Titlehuman dihydrofolate reductase complexed with NADPH and 5-{3-[3-(3,5-pyrimidine)]-phenyl-prop-1-yn-1-yl}-6-ethyl-pyrimidine-2,4diamine
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 / 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-25U / ETHANOL / Chem-NDP / AMMONIUM ION / STRONTIUM ION / Dihydrofolate reductase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.84 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 23, 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 1.3Sep 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_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_comp_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr2_label_atom_id / _pdbx_struct_conn_angle.ptnr2_label_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_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)45,59728
Polymers42,6992
Non-polymers2,89826
Water6,395355
1
A: Dihydrofolate reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,72212
Polymers21,3501
Non-polymers1,37211
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Dihydrofolate reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,87516
Polymers21,3501
Non-polymers1,52615
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)87.669, 93.784, 95.991
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221

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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: pET41(a+) / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P00374, dihydrofolate reductase

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Non-polymers , 8 types, 381 molecules

#2: Chemical ChemComp-25U / 6-ethyl-5-{3-[3-(pyrimidin-5-yl)phenyl]prop-1-yn-1-yl}pyrimidine-2,4-diamine


Mass: 330.386 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H18N6
#3: Chemical ChemComp-EOH / ETHANOL / Ethanol


Mass: 46.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O
#4: Chemical
ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Cl
#5: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: Mg
#6: Chemical ChemComp-NDP / NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / Nicotinamide adenine dinucleotide phosphate


Mass: 745.421 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H30N7O17P3
#7: Chemical ChemComp-SR / STRONTIUM ION / Strontium


Mass: 87.620 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Sr
#8: Chemical ChemComp-NH4 / AMMONIUM ION / Ammonium


Mass: 18.038 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: H4N
#9: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 355 / 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: 46.8 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 0.1M Tris-HCl, 0.2-0.3M Li2SO4, 25-32% (w/v) PEG 4000, 8% (v/v) ethanol, 11mM MgCl2, 11mM SrCl2, pH 7.5, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU / Wavelength: 1.54178 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Dec 2, 2011 / Details: Varimax optics
RadiationMonochromator: Copper anode / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 1.84→48 Å / Num. all: 34606 / Num. obs: 34606 / % possible obs: 100 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 4.2 % / Rmerge(I) obs: 0.071 / Net I/σ(I): 6.9
Reflection shellResolution: 1.84→1.91 Å / Redundancy: 4.11 % / Rmerge(I) obs: 0.317 / Mean I/σ(I) obs: 2.1 / % possible all: 100

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Processing

Software
NameVersionClassification
StructureStudiodata collection
PHASERphasing
PHENIX(phenix.refine: 1.8_1069)refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2C2S

2c2s


Resolution: 1.84→47.996 Å / SU ML: 0.29 / σ(F): 0.16 / Phase error: 30.89 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2772 1723 5 %
Rwork0.2274 --
obs0.2298 34451 99.5 %
all-34451 -
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.84→47.996 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3004 0 174 355 3533
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0033492
X-RAY DIFFRACTIONf_angle_d0.9554756
X-RAY DIFFRACTIONf_dihedral_angle_d16.7711400
X-RAY DIFFRACTIONf_chiral_restr0.064493
X-RAY DIFFRACTIONf_plane_restr0.004610
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.84-1.89420.39791380.30882686X-RAY DIFFRACTION100
1.8942-1.95530.35771440.312712X-RAY DIFFRACTION100
1.9553-2.02520.37451610.2862670X-RAY DIFFRACTION100
2.0252-2.10630.34751350.27552709X-RAY DIFFRACTION100
2.1063-2.20210.3391440.27082736X-RAY DIFFRACTION100
2.2021-2.31820.30521500.26052681X-RAY DIFFRACTION99
2.3182-2.46350.31741530.25042718X-RAY DIFFRACTION99
2.4635-2.65370.30391390.25012696X-RAY DIFFRACTION99
2.6537-2.92070.31351180.23712770X-RAY DIFFRACTION99
2.9207-3.34320.2541270.2172749X-RAY DIFFRACTION99
3.3432-4.21170.21611500.18642764X-RAY DIFFRACTION99
4.2117-48.0120.2411640.19682837X-RAY DIFFRACTION99

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