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- PDB-1dls: METHOTREXATE-RESISTANT VARIANTS OF HUMAN DIHYDROFOLATE REDUCTASE ... -

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Basic information

Entry
Database: PDB / ID: 1dls
TitleMETHOTREXATE-RESISTANT VARIANTS OF HUMAN DIHYDROFOLATE REDUCTASE WITH SUBSTITUTION OF LEUCINE 22: KINETICS, CRYSTALLOGRAPHY AND POTENTIAL AS SELECTABLE MARKERS
ComponentsDIHYDROFOLATE REDUCTASE
KeywordsOXIDOREDUCTASE / OXIDO-REDUCTASE
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 / Resolution: 2.3 Å
AuthorsCody, V. / Galitsky, N. / Luft, J.R. / Pangborn, W.
Citation
Journal: J.Biol.Chem. / Year: 1995
Title: Methotrexate-resistant variants of human dihydrofolate reductase with substitutions of leucine 22. Kinetics, crystallography, and potential as selectable markers.
Authors: Lewis, W.S. / Cody, V. / Galitsky, N. / Luft, J.R. / Pangborn, W. / Chunduru, S.K. / Spencer, H.T. / Appleman, J.R. / Blakley, R.L.
#1: Journal: J.Biol.Chem. / Year: 1994
Title: Methotrexate-Resistant Variants of Human Dihydrofolate Reductase: Effects of Phe-31 Substitutions
Authors: Chunduru, S.K. / Cody, V. / Luft, J.R. / Pangborn, W. / Appleman, J.R. / Blakley, R.L.
#2: Journal: Anti-Cancer Drug Des. / Year: 1992
Title: Crystal Structure Determination at 2.3 Angstroms of Recombinant Human Dihydrofolate Reductase Ternary Complex with Nadph and Methotrexate-Gamma-Tetrazole
Authors: Cody, V. / Luft, J.R. / Ciszak, E. / Kalman, T.I. / Freisheim, J.H.
History
DepositionJan 25, 1995Processing site: BNL
Revision 1.0Apr 20, 1995Provider: repository / Type: Initial release
Revision 1.1Mar 3, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Feb 7, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / struct_keywords / 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 / _pdbx_database_status.process_site / _struct_keywords.text / _struct_ref_seq_dif.details / _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

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Assembly

Deposited unit
A: DIHYDROFOLATE REDUCTASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,5993
Polymers21,4001
Non-polymers1,2002
Water2,000111
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)87.496, 87.496, 76.733
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number146
Space group name H-MH3
Atom site foot note1: CIS PROLINE - PRO 66
2: THE PEPTIDE BOND LINKING GLY 116 TO GLY 117 IS IN THE CIS CONFORMATION.

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Components

#1: Protein DIHYDROFOLATE REDUCTASE


Mass: 21399.541 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: POTENTIAL / 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.: 111 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.64 Å3/Da / Density % sol: 53.41 %
Crystal
*PLUS
Density % sol: 48 %
Crystal grow
*PLUS
pH: 8 / Method: vapor diffusion, hanging drop
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDDetails
20.1 Mphosphate1drop
362 %ammonium sulfate1drop
1NADPH1dropa molar excess of

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Data collection

RadiationScattering type: x-ray
Radiation wavelengthRelative weight: 1
ReflectionResolution: 2→8 Å / Num. obs: 11402 / % possible obs: 69 %

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Processing

SoftwareName: PROFFT / Classification: refinement
RefinementRfactor obs: 0.156 / Highest resolution: 2.3 Å
Refinement stepCycle: LAST / Highest resolution: 2.3 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1506 0 81 111 1698
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONp_bond_d0.0240.02
X-RAY DIFFRACTIONp_angle_d0.0540.04
X-RAY DIFFRACTIONp_angle_deg
X-RAY DIFFRACTIONp_planar_d0.0540.05
X-RAY DIFFRACTIONp_hb_or_metal_coord
X-RAY DIFFRACTIONp_mcbond_it2.321.75
X-RAY DIFFRACTIONp_mcangle_it3.312.5
X-RAY DIFFRACTIONp_scbond_it2.751.75
X-RAY DIFFRACTIONp_scangle_it4.272.5
X-RAY DIFFRACTIONp_plane_restr0.0180.02
X-RAY DIFFRACTIONp_chiral_restr0.190.15
X-RAY DIFFRACTIONp_singtor_nbd0.2040.5
X-RAY DIFFRACTIONp_multtor_nbd0.2610.5
X-RAY DIFFRACTIONp_xhyhbond_nbd0.2380.5
X-RAY DIFFRACTIONp_xyhbond_nbd
X-RAY DIFFRACTIONp_planar_tor3.13
X-RAY DIFFRACTIONp_staggered_tor19.715
X-RAY DIFFRACTIONp_orthonormal_tor21.415
X-RAY DIFFRACTIONp_transverse_tor
X-RAY DIFFRACTIONp_special_tor

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