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- PDB-1boz: STRUCTURE-BASED DESIGN AND SYNTHESIS OF LIPOPHILIC 2,4-DIAMINO-6-... -

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Basic information

Entry
Database: PDB / ID: 1boz
TitleSTRUCTURE-BASED DESIGN AND SYNTHESIS OF LIPOPHILIC 2,4-DIAMINO-6-SUBSTITUTED QUINAZOLINES AND THEIR EVALUATION AS INHIBITORS OF DIHYDROFOLATE REDUCTASE AND POTENTIAL ANTITUMOR AGENTS
ComponentsPROTEIN (DIHYDROFOLATE REDUCTASE)
KeywordsOXIDOREDUCTASE
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-NDP / Chem-PRD / Dihydrofolate reductase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsGangjee, A. / Vidwans, A.P. / Vasudevan, A. / Queener, S.F. / Kisliuk, R.L. / Cody, V. / Li, R. / Galitsky, N. / Luft, J.R. / Pangborn, W.
Citation
Journal: J.Med.Chem. / Year: 1998
Title: Structure-based design and synthesis of lipophilic 2,4-diamino-6-substituted quinazolines and their evaluation as inhibitors of dihydrofolate reductases and potential antitumor agents.
Authors: Gangjee, A. / Vidwans, A.P. / Vasudevan, A. / Queener, S.F. / Kisliuk, R.L. / Cody, V. / Li, R. / Galitsky, N. / Luft, J.R. / Pangborn, W.
#1: Journal: Acta Crystallogr.,Sect.D / Year: 1997
Title: Comparison of Ternary Complexes of Pneumocystis carinii and Wild-Type Human Dihydrofolate Reductase With a Novel Classical Antitumor Furo[2,3-d]pyrimidine Antifolate
Authors: Cody, V. / Galitsky, N. / Luft, J.R. / Pangborn, W. / Gangjee, A. / Devraj, R. / Queener, S.F. / Blakley, R.L.
#2: Journal: Biochemistry / Year: 1997
Title: Comparison of Two Independent Crystal Structures of Human Dihydrofolate Reductase Ternary Complexes Reduced with Nicotinamide Adenine Dinucleotide Phosphate and the Very Tight-Binding Inhibitor Pt523
Authors: Cody, V. / Galitsky, N. / Luft, J.R. / Pangborn, W. / Rosowsky, A. / Blakley, R.L.
History
DepositionAug 6, 1998Deposition site: BNL / Processing site: RCSB
Revision 1.0Aug 12, 1998Provider: repository / Type: Initial release
Revision 1.1Apr 27, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Oct 4, 2017Group: Refinement description / Category: software
Revision 1.4Dec 21, 2022Group: 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 1.5May 22, 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: PROTEIN (DIHYDROFOLATE REDUCTASE)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,3453
Polymers21,2591
Non-polymers1,0862
Water2,252125
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)86.259, 86.259, 77.637
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 PROTEIN (DIHYDROFOLATE REDUCTASE)


Mass: 21259.402 Da / Num. of mol.: 1 / Mutation: F31G / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / 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-PRD / N6-(2,5-DIMETHOXY-BENZYL)-N6-METHYL-PYRIDO[2,3-D]PYRIMIDINE-2,4,6-TRIAMINE


Mass: 340.380 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H20N6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 125 / 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: 2.61 Å3/Da / Density % sol: 52.93 %
Crystal growpH: 6.5 / Details: pH 6.5
Crystal grow
*PLUS
Temperature: 4 ℃ / pH: 7 / Method: vapor diffusion, hanging drop
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-ID
162 %ammonium sulfate1drop
20.1 Mphosphate1drop

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Data collection

DiffractionMean temperature: 287 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU200 / Wavelength: 1.5418
DetectorType: RIGAKU RAXIS / Detector: IMAGE PLATE
RadiationMonochromator: NI FILTER / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.1→53 Å / Num. obs: 9706 / % possible obs: 95 % / Observed criterion σ(I): 2 / Redundancy: 2.5 % / Rmerge(I) obs: 0.049
Reflection shellHighest resolution: 2.1 Å / Redundancy: 2.5 % / Rmerge(I) obs: 0.125 / % possible all: 78
Reflection
*PLUS
% possible obs: 86.4 % / Rmerge(I) obs: 0.0496
Reflection shell
*PLUS
Highest resolution: 2 Å / Lowest resolution: 2.1 Å / % possible obs: 63.6 %

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Processing

Software
NameClassification
PROLSQrefinement
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→8 Å / Cross valid method: THROUGHOUT / σ(F): 2
RfactorNum. reflection% reflection
Rwork0.202 --
obs-8970 95 %
Displacement parametersBiso mean: 19.34 Å2
Refinement stepCycle: LAST / Resolution: 2.1→8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1495 0 73 125 1693
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONp_bond_d0.0180.02
X-RAY DIFFRACTIONp_angle_d0.05
X-RAY DIFFRACTIONp_angle_deg
X-RAY DIFFRACTIONp_planar_d0.0510.05
X-RAY DIFFRACTIONp_hb_or_metal_coord
X-RAY DIFFRACTIONp_mcbond_it
X-RAY DIFFRACTIONp_mcangle_it
X-RAY DIFFRACTIONp_scbond_it
X-RAY DIFFRACTIONp_scangle_it
X-RAY DIFFRACTIONp_plane_restr0.0140.02
X-RAY DIFFRACTIONp_chiral_restr0.1910.15
X-RAY DIFFRACTIONp_singtor_nbd0.1970.5
X-RAY DIFFRACTIONp_multtor_nbd0.2620.5
X-RAY DIFFRACTIONp_xhyhbond_nbd
X-RAY DIFFRACTIONp_xyhbond_nbd0.2590.5
X-RAY DIFFRACTIONp_planar_tor2.43
X-RAY DIFFRACTIONp_staggered_tor19.415
X-RAY DIFFRACTIONp_orthonormal_tor
X-RAY DIFFRACTIONp_transverse_tor22.515
X-RAY DIFFRACTIONp_special_tor
Software
*PLUS
Name: PROLSQ / Classification: refinement
Refinement
*PLUS
Highest resolution: 2.1 Å / σ(F): 2 / Rfactor obs: 0.202
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal targetDev ideal
X-RAY DIFFRACTIONp_bond_d0.02
X-RAY DIFFRACTIONp_angle_d0.05
X-RAY DIFFRACTIONp_planar_d0.05

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