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- PDB-4kak: Crystal structure of human dihydrofolate reductase complexed with... -

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Basic information

Entry
Database: PDB / ID: 4kak
TitleCrystal structure of human dihydrofolate reductase complexed with NADPH and 6-ethyl-5-[(3S)-3-[3-methoxy-5-(pyridine-4-yl)phenyl]but-1-yn-1-yl]pyrimidine-2,4-diamine (UCP1006)
ComponentsDihydrofolate reductase
KeywordsOxidoreductase/oxidoreductase inhibitor / Oxidoreductase / 5 / 6 / 7 / 8-tetrahydrofolate / NADP+ / 8-dihydrofolate / Hydride shift / 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-06U / ETHANOL / Chem-NDP / Dihydrofolate reductase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.8 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 22, 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.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)45,32715
Polymers42,6992
Non-polymers2,62813
Water6,251347
1
A: Dihydrofolate reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,6477
Polymers21,3501
Non-polymers1,2976
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Dihydrofolate reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,6818
Polymers21,3501
Non-polymers1,3317
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)88.077, 93.634, 96.039
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-346-

HOH

21A-405-

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) / Strain: RP11-399L5 / 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 , 5 types, 360 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-06U / 6-ethyl-5-{(3R)-3-[3-methoxy-5-(pyridin-4-yl)phenyl]but-1-yn-1-yl}pyrimidine-2,4-diamine


Mass: 373.451 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H23N5O
#4: Chemical
ChemComp-EOH / ETHANOL


Mass: 46.068 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6O
#5: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Ca
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 347 / 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: 2.32 Å3/Da / Density % sol: 46.99 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 0.1M Tris-HCl pH 7.4, 0.2M Lithium sulfate, 30% (w/v) PEG 4000, 8% (v/v) ethanol, 11mM CaCl2, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Jun 11, 2011 / Details: Varimax optics
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.8→46.82 Å / Num. all: 37102 / Num. obs: 37016 / % possible obs: 99.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.95 % / Biso Wilson estimate: 31.21 Å2 / Rmerge(I) obs: 0.061 / Net I/σ(I): 8.3
Reflection shellResolution: 1.8→1.86 Å / Redundancy: 3.88 % / Rmerge(I) obs: 0.492 / Mean I/σ(I) obs: 1 / Rsym value: 0.554

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Processing

Software
NameVersionClassification
StructureStudiodata collection
PHASERfor MRphasing
PHENIXrefinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2C2S

2c2s


Resolution: 1.8→32.077 Å / Occupancy max: 1 / Occupancy min: 0.16 / FOM work R set: 0.7549 / SU ML: 0.27 / Phase error: 30.18 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflection
Rfree0.2685 1845 5 %
Rwork0.223 35078 -
obs0.2253 36923 99.55 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 18.1734 Å2
Refinement stepCycle: LAST / Resolution: 1.8→32.077 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3004 0 171 347 3522
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 13

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.8001-1.84870.38691520.331826392791100
1.8487-1.90310.37921360.3312655279199
1.9031-1.96450.33141300.310226912821100
1.9645-2.03470.43511220.307827062828100
2.0347-2.11620.33361290.273726652794100
2.1162-2.21250.30761310.270927122843100
2.2125-2.32910.33511500.27422675282599
2.3291-2.4750.31721490.256226982847100
2.475-2.6660.30961390.250327012840100
2.666-2.93410.30381420.24926922834100
2.9341-3.35830.2861580.218527062864100
3.3583-4.22950.21531600.16662722288299
4.2295-32.08230.18851470.17162816296398

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