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- PDB-1sej: Crystal Structure of Dihydrofolate Reductase-Thymidylate Synthase... -

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Basic information

Entry
Database: PDB / ID: 1sej
TitleCrystal Structure of Dihydrofolate Reductase-Thymidylate Synthase from Cryptosporidium hominis Bound to 1843U89/NADPH/dUMP
Componentsbifunctional dihydrofolate reductase-thymidylate synthase
KeywordsTRANSFERASE / OXIDOREDUCTASE / bifunctional enzyme
Function / homology
Function and homology information


thymidylate synthase activity / dTMP biosynthetic process / dihydrofolate reductase activity / tetrahydrofolate biosynthetic process / one-carbon metabolic process / methylation / nucleotide binding
Similarity search - Function
Bifunctional dihydrofolate reductase/thymidylate synthase / Thymidylate Synthase; Chain A / Thymidylate synthase/dCMP hydroxymethylase domain / Thymidylate synthase/dCMP hydroxymethylase / Thymidylate synthase, active site / Thymidylate synthase active site. / Thymidylate synthase / Thymidylate synthase/dCMP hydroxymethylase domain / Thymidylate synthase/dCMP hydroxymethylase superfamily / Thymidylate synthase ...Bifunctional dihydrofolate reductase/thymidylate synthase / Thymidylate Synthase; Chain A / Thymidylate synthase/dCMP hydroxymethylase domain / Thymidylate synthase/dCMP hydroxymethylase / Thymidylate synthase, active site / Thymidylate synthase active site. / Thymidylate synthase / Thymidylate synthase/dCMP hydroxymethylase domain / Thymidylate synthase/dCMP hydroxymethylase superfamily / Thymidylate synthase / Dihydrofolate Reductase, subunit A / Dihydrofolate Reductase, subunit A / Dihydrofolate reductase conserved site / Dihydrofolate reductase (DHFR) domain signature. / Dihydrofolate reductase domain / Dihydrofolate reductase / Dihydrofolate reductase (DHFR) domain profile. / Dihydrofolate reductase-like domain superfamily / 2-Layer Sandwich / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-F89 / Chem-NDP / 2'-DEOXYURIDINE 5'-MONOPHOSPHATE / Bifunctional dihydrofolate reductase-thymidylate synthase
Similarity search - Component
Biological speciesCryptosporidium hominis (eukaryote)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.87 Å
AuthorsAnderson, A.C.
CitationJournal: Acta Crystallogr.,Sect.F / Year: 2005
Title: Two crystal structures of dihydrofolate reductase-thymidylate synthase from Cryptosporidium hominis reveal protein-ligand interactions including a structural basis for observed antifolate resistance.
Authors: Anderson, A.C.
History
DepositionFeb 17, 2004Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 18, 2004Provider: repository / Type: Initial release
Revision 1.1Apr 29, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Oct 11, 2017Group: Refinement description / Category: software / Item: _software.classification / _software.name
Revision 1.4Aug 23, 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 / 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

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Assembly

Deposited unit
A: bifunctional dihydrofolate reductase-thymidylate synthase
B: bifunctional dihydrofolate reductase-thymidylate synthase
C: bifunctional dihydrofolate reductase-thymidylate synthase
D: bifunctional dihydrofolate reductase-thymidylate synthase
E: bifunctional dihydrofolate reductase-thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)311,58625
Polymers301,3135
Non-polymers10,27320
Water6,648369
1
A: bifunctional dihydrofolate reductase-thymidylate synthase
B: bifunctional dihydrofolate reductase-thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)124,63410
Polymers120,5252
Non-polymers4,1098
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area16470 Å2
ΔGint-52 kcal/mol
Surface area38360 Å2
MethodPISA
2
C: bifunctional dihydrofolate reductase-thymidylate synthase
D: bifunctional dihydrofolate reductase-thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)124,63410
Polymers120,5252
Non-polymers4,1098
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area16450 Å2
ΔGint-52 kcal/mol
Surface area38400 Å2
MethodPISA
3
E: bifunctional dihydrofolate reductase-thymidylate synthase
hetero molecules

E: bifunctional dihydrofolate reductase-thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)124,63410
Polymers120,5252
Non-polymers4,1098
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_457-x-1,y,-z+21
Unit cell
Length a, b, c (Å)214.900, 116.300, 219.700
Angle α, β, γ (deg.)90.00, 95.23, 90.00
Int Tables number5
Space group name H-MC121
DetailsThis entry contains the crystallographic asymmetric unit which consists of 5 chains. The biological unit is a dimer. Chains A,B and C,D form two dimers. Chain E is on a crystallographic two-fold, its monomer partner is formed across this two-fold.

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Components

#1: Protein
bifunctional dihydrofolate reductase-thymidylate synthase


Mass: 60262.520 Da / Num. of mol.: 5
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Cryptosporidium hominis (eukaryote) / Production host: Escherichia coli (E. coli) / Strain (production host): PA414
References: UniProt: Q27552, thymidylate synthase, dihydrofolate reductase
#2: Chemical
ChemComp-UMP / 2'-DEOXYURIDINE 5'-MONOPHOSPHATE / DUMP / Deoxyuridine monophosphate


Mass: 308.182 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C9H13N2O8P
#3: Chemical
ChemComp-F89 / S)-2-(5(((1,2-DIHYDRO-3-METHYL-1-OXOBENZO(F)QUINAZOLIN-9-YL)METHYL)AMINO)1-OXO-2-ISOINDOLINYL)GLUTARIC ACID / FOLATE ANALOG 1843U89


Mass: 500.503 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: C27H24N4O6
#4: Chemical
ChemComp-NDP / NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / Nicotinamide adenine dinucleotide phosphate


Mass: 745.421 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C21H30N7O17P3
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 369 / 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: 4.47 Å3/Da / Density % sol: 72.29 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8.4
Details: PEG 6000, lithium sulfate, ammonium sulfate, Tris, pH 8.4, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL7-1 / Wavelength: 1 Å
DetectorType: MARRESEARCH / Detector: IMAGE PLATE / Date: Jul 18, 1998 / Details: mirror
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.87→50 Å / Num. all: 119034 / Num. obs: 111987 / % possible obs: 81 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 4.5 % / Biso Wilson estimate: 66.3 Å2 / Rmerge(I) obs: 0.105 / Rsym value: 0.105 / Net I/σ(I): 8.6
Reflection shellResolution: 2.87→2.98 Å / Redundancy: 4 % / Rmerge(I) obs: 0.386 / Mean I/σ(I) obs: 1.9 / Num. unique all: 12048 / Rsym value: 0.386 / % possible all: 90

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Processing

Software
NameVersionClassification
CNS1.1refinement
MAR345data collection
SCALEPACKdata scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1qzf

1qzf


Resolution: 2.87→45.15 Å / Rfactor Rfree error: 0.002 / Data cutoff high absF: 3654354.42 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.237 11185 10 %RANDOM
Rwork0.22 ---
all0.22 111987 --
obs0.22 111987 90.4 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 15.5047 Å2 / ksol: 0.318839 e/Å3
Displacement parametersBiso mean: 33.6 Å2
Baniso -1Baniso -2Baniso -3
1-0.3 Å20 Å2-7.41 Å2
2--4.58 Å20 Å2
3----4.88 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.4 Å0.37 Å
Luzzati d res low-5 Å
Luzzati sigma a0.55 Å0.53 Å
Refinement stepCycle: LAST / Resolution: 2.87→45.15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms21115 0 710 369 22194
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.008
X-RAY DIFFRACTIONc_angle_deg1.6
X-RAY DIFFRACTIONc_dihedral_angle_d24.2
X-RAY DIFFRACTIONc_improper_angle_d2.16
X-RAY DIFFRACTIONc_mcbond_it0.911.5
X-RAY DIFFRACTIONc_mcangle_it1.62
X-RAY DIFFRACTIONc_scbond_it1.192
X-RAY DIFFRACTIONc_scangle_it1.92.5
LS refinement shellResolution: 2.87→2.98 Å / Rfactor Rfree error: 0.011 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.337 990 9.8 %
Rwork0.334 9113 -
obs-12048 45.8 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2HCPLIGS_NDPDUBW.PARHCPLIGS_NDPDUBW.TOP
X-RAY DIFFRACTION3WATER_REP.PARAMWATER.TOP

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