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- PDB-1u70: Understanding the Role of Leu22 Variants in Methotrexate Resistan... -

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Basic information

Entry
Database: PDB / ID: 1u70
TitleUnderstanding the Role of Leu22 Variants in Methotrexate Resistance: Comparison of Wild-type and Leu22Arg Variant Mouse and Human Dihydrofolate Reductase
ComponentsDihydrofolate reductase
KeywordsOXIDOREDUCTASE / variant DHFR mouse / human
Function / homology
Function and homology information


Metabolism of folate and pterines / regulation of removal of superoxide radicals / dihydrofolic acid binding / tetrahydrobiopterin biosynthetic process / tetrahydrofolate metabolic process / sequence-specific mRNA binding / response to methotrexate / tetrahydrofolate interconversion / axon regeneration / folic acid binding ...Metabolism of folate and pterines / regulation of removal of superoxide radicals / dihydrofolic acid binding / tetrahydrobiopterin biosynthetic process / tetrahydrofolate metabolic process / sequence-specific mRNA binding / response to methotrexate / tetrahydrofolate interconversion / axon regeneration / folic acid binding / dihydrofolate metabolic process / glycine biosynthetic process / dihydrofolate reductase / folic acid metabolic process / dihydrofolate reductase activity / NADPH binding / tetrahydrofolate biosynthetic process / mRNA regulatory element binding translation repressor activity / positive regulation of nitric-oxide synthase activity / response to nicotine / NADP binding / mitochondrial inner membrane / mitochondrial matrix / mRNA binding / mitochondrion / nucleus / cytosol / cytoplasm
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 speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.5 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, 2018Group: Experimental preparation / Category: exptl_crystal_grow
Item: _exptl_crystal_grow.pdbx_details / _exptl_crystal_grow.temp
Revision 1.4Oct 20, 2021Group: Database references / Derived calculations / Category: database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.5Feb 14, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Dihydrofolate reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,7483
Polymers21,5481
Non-polymers1,2002
Water48627
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)42.016, 61.536, 43.572
Angle α, β, γ (deg.)90.00, 116.69, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Dihydrofolate reductase /


Mass: 21547.881 Da / Num. of mol.: 1 / Fragment: mouse DHFR / Mutation: L22R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Dhfr / Production host: Escherichia coli (E. coli) / References: UniProt: P00375, dihydrofolate reductase
#2: Chemical ChemComp-MTX / METHOTREXATE / Methotrexate


Mass: 454.439 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H22N8O5 / Comment: chemotherapy*YM
#3: Chemical ChemComp-NDP / NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / Nicotinamide adenine dinucleotide phosphate


Mass: 745.421 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H30N7O17P3
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 27 / 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

Crystal
IDDensity Matthews (Å3/Da)Density % sol (%)
12.3447.34
2
Crystal grow
Temperature (K)Crystal-IDMethodpHDetails
2981vapor diffusion, hanging drop7.520% PEG 4k 0.1 M HEPES, pH 7.5, VAPOR DIFFUSION, HANGING DROP, temperature 298K
2982vapor diffusion, hanging drop762% AS, 0.1M phosphate , pH 7.0, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 298 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU300 / Wavelength: 1.5418
DetectorType: RIGAKU RAXIS IIC / Detector: IMAGE PLATE / Date: Jun 25, 1997 / Details: mirrors
RadiationMonochromator: graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.5→50 Å / Num. all: 6963 / Num. obs: 6792 / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Rmerge(I) obs: 0.055
Reflection shellResolution: 2.5→2.56 Å / % possible all: 96.1

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Processing

Software
NameClassification
DENZOdata reduction
SCALEPACKdata scaling
PROTEINmodel building
PROFFTrefinement
PROTEINphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.5→50 Å / Isotropic thermal model: isotropic / σ(F): 2 / Stereochemistry target values: Engh & Huber
RfactorNum. reflectionSelection details
Rfree0.225 217 two sigma cutoff
Rwork0.183 --
all0.225 6963 -
obs0.225 6792 -
Displacement parametersBiso mean: 39.6 Å2
Refinement stepCycle: LAST / Resolution: 2.5→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1516 0 81 27 1624
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONp_bond_d0.017
X-RAY DIFFRACTIONp_angle_d0.064
X-RAY DIFFRACTIONp_mcangle_it0.069
X-RAY DIFFRACTIONp_mcbond_it0.247

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