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- PDB-1hvy: Human thymidylate synthase complexed with dUMP and Raltitrexed, a... -

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Basic information

Entry
Database: PDB / ID: 1hvy
TitleHuman thymidylate synthase complexed with dUMP and Raltitrexed, an antifolate drug, is in the closed conformation
ComponentsTHYMIDYLATE SYNTHASE
KeywordsTRANSFERASE / Tomudex / Raltitrexed
Function / homology
Function and homology information


uracil metabolic process / response to organophosphorus / intestinal epithelial cell maturation / response to folic acid / Interconversion of nucleotide di- and triphosphates / response to vitamin A / thymidylate synthase / sequence-specific mRNA binding / cartilage development / tetrahydrofolate interconversion ...uracil metabolic process / response to organophosphorus / intestinal epithelial cell maturation / response to folic acid / Interconversion of nucleotide di- and triphosphates / response to vitamin A / thymidylate synthase / sequence-specific mRNA binding / cartilage development / tetrahydrofolate interconversion / thymidylate synthase activity / folic acid binding / dTMP biosynthetic process / dTTP biosynthetic process / G1/S-Specific Transcription / DNA biosynthetic process / developmental growth / response to glucocorticoid / mRNA regulatory element binding translation repressor activity / response to progesterone / response to cytokine / liver regeneration / response to toxic substance / circadian rhythm / methylation / response to ethanol / mitochondrial inner membrane / negative regulation of translation / mitochondrial matrix / response to xenobiotic stimulus / protein homodimerization activity / mitochondrion / nucleus / cytosol / cytoplasm
Similarity search - Function
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 / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
BETA-MERCAPTOETHANOL / TOMUDEX / 2'-DEOXYURIDINE 5'-MONOPHOSPHATE / Thymidylate synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsPhan, J. / Koli, S. / Minor, W. / Dunlap, R.B. / Berger, S.H. / Lebioda, L.
CitationJournal: Biochemistry / Year: 2001
Title: Human thymidylate synthase is in the closed conformation when complexed with dUMP and raltitrexed, an antifolate drug
Authors: Phan, J. / Koli, S. / Minor, W. / Dunlap, R.B. / Berger, S.H. / Lebioda, L.
History
DepositionJan 8, 2001Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 31, 2001Provider: repository / Type: Initial release
Revision 1.1Apr 27, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Oct 10, 2012Group: Non-polymer description
Revision 1.4Oct 4, 2017Group: Refinement description / Category: software
Revision 1.5Apr 13, 2022Group: Database references / Derived calculations / Structure summary
Category: audit_author / citation_author ...audit_author / citation_author / database_2 / struct_conn / struct_ref_seq_dif / struct_site
Item: _audit_author.identifier_ORCID / _citation_author.identifier_ORCID ..._audit_author.identifier_ORCID / _citation_author.identifier_ORCID / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _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

Downloads & links

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Assembly

Deposited unit
A: THYMIDYLATE SYNTHASE
B: THYMIDYLATE SYNTHASE
C: THYMIDYLATE SYNTHASE
D: THYMIDYLATE SYNTHASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)135,82716
Polymers132,4484
Non-polymers3,37912
Water10,737596
1
A: THYMIDYLATE SYNTHASE
B: THYMIDYLATE SYNTHASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,9148
Polymers66,2242
Non-polymers1,6906
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8080 Å2
ΔGint-32 kcal/mol
Surface area21530 Å2
MethodPISA
2
C: THYMIDYLATE SYNTHASE
D: THYMIDYLATE SYNTHASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,9148
Polymers66,2242
Non-polymers1,6906
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8110 Å2
ΔGint-36 kcal/mol
Surface area21670 Å2
MethodPISA
Unit cell
Length a, b, c (Å)68.849, 70.495, 74.533
Angle α, β, γ (deg.)70.23, 83.29, 73.28
Int Tables number1
Space group name H-MP1

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Components

#1: Protein
THYMIDYLATE SYNTHASE /


Mass: 33111.969 Da / Num. of mol.: 4 / Fragment: RESIDUES 26-313
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli) / Strain (production host): TX61 / References: UniProt: P04818, thymidylate synthase
#2: Chemical
ChemComp-D16 / TOMUDEX / ZD1694 / Raltitrexed / Raltitrexed


Mass: 458.488 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H22N4O6S / Comment: chemotherapy, inhibitor*YM
#3: Chemical
ChemComp-UMP / 2'-DEOXYURIDINE 5'-MONOPHOSPHATE / DUMP / Deoxyuridine monophosphate


Mass: 308.182 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C9H13N2O8P
#4: Chemical
ChemComp-BME / BETA-MERCAPTOETHANOL / 2-Mercaptoethanol


Mass: 78.133 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6OS
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 596 / 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: 2.46 Å3/Da / Density % sol: 50.02 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8.8
Details: PEG 4000, EDTA, Tris buffer, Ammonium Sulfate , pH 8.8, VAPOR DIFFUSION, HANGING DROP, temperature 298K
Crystal grow
*PLUS
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDDetails
12.65 mg/mlprotein1drop
20.5 mMEDTA1drop
315 mM2-mercaptoethanol1drop
4100 mMTris-base1droppH8.8
520 %PEG40001drop
61 %satammonium sulfate1drop
750 mMTris-HCl1drop
840 %PEG40001reservoir
92 %satammonium sulfate1reservoir
1020 mM2-mercaptoethanol1reservoir
11100 mMTris-HCl1reservoirpH7.6

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Data collection

DiffractionMean temperature: 120 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU200 / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Jun 15, 1998
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.9→6 Å / Num. all: 94011 / Num. obs: 89364 / % possible obs: 95 % / Observed criterion σ(F): 3 / Observed criterion σ(I): 1 / Redundancy: 2.4 % / Biso Wilson estimate: 10.5 Å2 / Rmerge(I) obs: 0.072 / Net I/σ(I): 11.8
Reflection shellResolution: 1.9→1.96 Å / Rmerge(I) obs: 0.34 / Num. unique all: 8643 / % possible all: 87
Reflection
*PLUS
Num. measured all: 229821

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Processing

Software
NameClassification
SCALEPACKdata scaling
CNSrefinement
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.9→20.09 Å / Rfactor Rfree error: 0.003 / Data cutoff high absF: 1463303.69 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 3 / σ(I): 1 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.244 5566 7.1 %RANDOM
Rwork0.201 ---
obs0.201 78861 79.2 %-
all-94011 --
Solvent computationSolvent model: FLAT MODEL / Bsol: 38.58 Å2 / ksol: 0.35 e/Å3
Displacement parametersBiso mean: 21.9 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.28 Å0.23 Å
Luzzati d res low-5 Å
Luzzati sigma a0.25 Å0.17 Å
Refinement stepCycle: LAST / Resolution: 1.9→20.09 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9316 0 224 596 10136
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.008
X-RAY DIFFRACTIONc_angle_deg1.4
X-RAY DIFFRACTIONc_dihedral_angle_d23.3
X-RAY DIFFRACTIONc_improper_angle_d0.78
X-RAY DIFFRACTIONc_mcbond_it1.561.5
X-RAY DIFFRACTIONc_mcangle_it1.992
X-RAY DIFFRACTIONc_scbond_it1.882
X-RAY DIFFRACTIONc_scangle_it2.712.5
LS refinement shellResolution: 1.9→2.02 Å / Rfactor Rfree error: 0.012 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.288 589 6.4 %
Rwork0.233 8562 -
obs-8643 55.1 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2WATER_REP.PARAMWATER.TOP
X-RAY DIFFRACTION3DUMPZD1694BME.PARAMDUMPZD1694BME.TOP
Software
*PLUS
Name: CNS / Version: 1 / Classification: refinement
Refinement
*PLUS
σ(F): 3 / % reflection Rfree: 7.1 %
Solvent computation
*PLUS
Displacement parameters
*PLUS
Biso mean: 21.9 Å2
Refine LS restraints
*PLUS
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_angle_deg1.4
X-RAY DIFFRACTIONc_dihedral_angle_d
X-RAY DIFFRACTIONc_dihedral_angle_deg23.3
X-RAY DIFFRACTIONc_improper_angle_d
X-RAY DIFFRACTIONc_improper_angle_deg0.78
X-RAY DIFFRACTIONc_mcbond_it1.5
X-RAY DIFFRACTIONc_scbond_it2
X-RAY DIFFRACTIONc_mcangle_it2
X-RAY DIFFRACTIONc_scangle_it2.5
LS refinement shell
*PLUS
Rfactor Rfree: 0.288 / % reflection Rfree: 6.4 % / Rfactor Rwork: 0.233

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