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- PDB-1u72: Understanding the Role of Leu22 Variants in Methotrexate Resistan... -

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Basic information

Entry
Database: PDB / ID: 1u72
TitleUnderstanding the Role of Leu22 Variants in Methotrexate Resistance: Comparison of Wild-type and Leu22Arg Variant Mouse and Human Dihydrfolate Reductase Ternary Crystal Complexes with Methotrexate and NADPH
ComponentsDihydrofolate reductase
KeywordsOXIDOREDUCTASE / wild type humand DHFR
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 / folic acid metabolic 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
METHOTREXATE / Chem-NDP / Dihydrofolate reductase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsCody, V.
CitationJournal: Acta Crystallogr.,Sect.D / Year: 2005
Title: Understanding the role of Leu22 variants in methotrexate resistance: comparison of wild-type and Leu22Arg variant mouse and human dihydrofolate reductase ternary crystal complexes with methotrexate and NADPH.
Authors: Cody, V. / Luft, J.R. / Pangborn, W.
History
DepositionAug 2, 2004Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 1, 2005Provider: repository / Type: Initial release
Revision 1.1Apr 30, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Feb 14, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,5493
Polymers21,3501
Non-polymers1,2002
Water82946
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)87.379, 87.379, 76.721
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number146
Space group name H-MH3

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Components

#1: Protein Dihydrofolate reductase


Mass: 21349.525 Da / Num. of mol.: 1 / Fragment: human DHFR
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DHFR / Production host: Escherichia coli (E. coli) / References: UniProt: P00374, dihydrofolate reductase
#2: Chemical ChemComp-NDP / NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE


Mass: 745.421 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H30N7O17P3
#3: Chemical ChemComp-MTX / METHOTREXATE


Mass: 454.439 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H22N8O5 / Comment: chemotherapy*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 46 / 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: 2.64 Å3/Da / Density % sol: 53.41 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8
Details: 63% AS, 0.1 M phoshate pH 8.0 , VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 298 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU300 / Wavelength: 1.5414 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Feb 6, 1998 / Details: mirrors
RadiationMonochromator: graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5414 Å / Relative weight: 1
ReflectionResolution: 1.9→50 Å / Num. all: 8361 / Num. obs: 6408 / % possible obs: 90.3 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Biso Wilson estimate: 26.5 Å2 / Rmerge(I) obs: 0.049
Reflection shellResolution: 1.9→2 Å / % possible all: 55.9

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Processing

Software
NameClassification
DENZOdata reduction
SCALEPACKdata scaling
PROTEINmodel building
PROLSQrefinement
PROTEINphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.9→50 Å / σ(F): 2 / Stereochemistry target values: Engh & Huber
RfactorNum. reflectionSelection details
Rfree0.213 -Random
Rwork0.159 --
all-6408 -
obs-6203 -
Refinement stepCycle: LAST / Resolution: 1.9→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1502 0 81 46 1629
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONp_bond_d
X-RAY DIFFRACTIONo_mcbond_it0.053
X-RAY DIFFRACTIONp_mcbond_it0.053
X-RAY DIFFRACTIONp_mcangle_it0.231

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