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- PDB-6oju: Crystal structure of human thymidylate synthase Delta (7-29) in c... -

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Basic information

Entry
Database: PDB / ID: 6oju
TitleCrystal structure of human thymidylate synthase Delta (7-29) in complex with dUMP and 2-amino-4-oxo-4,7-dihydro-pyrrolo[2,3-d]pyrimidine-methyl-phenyl-D-glutamic acid
ComponentsThymidylate synthase,Thymidylate synthase
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Inhibitor / TS-DHFR / TRANSFERASE / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


thymidylate synthase / Interconversion of nucleotide di- and triphosphates / sequence-specific mRNA binding / folic acid binding / thymidylate synthase activity / tetrahydrofolate interconversion / dTMP biosynthetic process / dTTP biosynthetic process / DNA biosynthetic process / G1/S-Specific Transcription ...thymidylate synthase / Interconversion of nucleotide di- and triphosphates / sequence-specific mRNA binding / folic acid binding / thymidylate synthase activity / tetrahydrofolate interconversion / dTMP biosynthetic process / dTTP biosynthetic process / DNA biosynthetic process / G1/S-Specific Transcription / mRNA regulatory element binding translation repressor activity / methylation / negative regulation of translation / mitochondrial inner membrane / mitochondrial matrix / mitochondrion / nucleus / cytosol / cytoplasm
Similarity search - Function
Thymidylate Synthase; Chain A / Thymidylate synthase/dCMP hydroxymethylase domain / Thymidylate synthase, active site / Thymidylate synthase active site. / Thymidylate synthase / Thymidylate synthase/dCMP hydroxymethylase / Thymidylate synthase/dCMP hydroxymethylase domain / Thymidylate synthase/dCMP hydroxymethylase superfamily / Thymidylate synthase / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-D96 / 2'-DEOXYURIDINE 5'-MONOPHOSPHATE / Thymidylate synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.884 Å
AuthorsCzyzyk, D.J. / Anderson, K.S. / Valhondo, M. / Jorgensen, W.L.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI083146 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)5T32AI007404 United States
CitationJournal: Febs Lett. / Year: 2019
Title: Understanding the structural basis of species selective, stereospecific inhibition for Cryptosporidium and human thymidylate synthase.
Authors: Czyzyk, D.J. / Valhondo, M. / Jorgensen, W.L. / Anderson, K.S.
History
DepositionApr 12, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 19, 2019Provider: repository / Type: Initial release
Revision 1.1Aug 21, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.2Dec 18, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
B: Thymidylate synthase,Thymidylate synthase
A: Thymidylate synthase,Thymidylate synthase
C: Thymidylate synthase,Thymidylate synthase
D: Thymidylate synthase,Thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)135,64312
Polymers132,7564
Non-polymers2,8868
Water61334
1
B: Thymidylate synthase,Thymidylate synthase
D: Thymidylate synthase,Thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,8216
Polymers66,3782
Non-polymers1,4434
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: Thymidylate synthase,Thymidylate synthase
C: Thymidylate synthase,Thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,8216
Polymers66,3782
Non-polymers1,4434
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
B: Thymidylate synthase,Thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,9113
Polymers33,1891
Non-polymers7222
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
A: Thymidylate synthase,Thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,9113
Polymers33,1891
Non-polymers7222
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
5
C: Thymidylate synthase,Thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,9113
Polymers33,1891
Non-polymers7222
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
6
D: Thymidylate synthase,Thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,9113
Polymers33,1891
Non-polymers7222
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)62.097, 124.853, 80.364
Angle α, β, γ (deg.)90.00, 92.12, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein
Thymidylate synthase,Thymidylate synthase / TSase


Mass: 33189.070 Da / Num. of mol.: 4 / Fragment: residues 30-313
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TYMS, TS, OK/SW-cl.29 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / Variant (production host): TX-61 / References: UniProt: P04818, thymidylate synthase
#2: Chemical
ChemComp-UMP / 2'-DEOXYURIDINE 5'-MONOPHOSPHATE / DUMP


Mass: 308.182 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: C9H13N2O8P
#3: Chemical
ChemComp-D96 / N-{4-[(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)methyl]benzene-1-carbonyl}-D-glutamic acid


Mass: 413.384 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C19H19N5O6
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 34 / 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: 2.39 Å3/Da / Density % sol: 48.5 %
Crystal growTemperature: 295.15 K / Method: vapor diffusion, sitting drop / pH: 5
Details: Well solution 0.1 M Na Acetate, 1.55 M Na formate Seed Solution (diluted 50:1) 0.2 M MgCl2, 20 % PEG 3350 Drop ratio 3:2:1 Enzyme mix/well solution/ seed solution

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-C / Wavelength: 0.9792 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Feb 12, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9792 Å / Relative weight: 1
ReflectionResolution: 2.88→50 Å / Num. obs: 27262 / % possible obs: 98.6 % / Redundancy: 6.8 % / CC1/2: 0.984 / Rsym value: 0.227 / Net I/σ(I): 4.99
Reflection shellResolution: 2.88→3.06 Å / Redundancy: 6.7 % / Mean I/σ(I) obs: 2.11 / Num. unique obs: 4185 / CC1/2: 0.842 / Rsym value: 0.963 / % possible all: 94.5

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Processing

Software
NameVersionClassification
PHENIX(1.10.1_2155)refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1HZW

1hzw


Resolution: 2.884→49.287 Å / SU ML: 0.47 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 29.69
RfactorNum. reflection% reflection
Rfree0.2494 1358 4.99 %
Rwork0.2131 --
obs0.2149 27202 98.39 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.884→49.287 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8758 0 200 34 8992
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0029195
X-RAY DIFFRACTIONf_angle_d0.51212537
X-RAY DIFFRACTIONf_dihedral_angle_d8.7095294
X-RAY DIFFRACTIONf_chiral_restr0.0411356
X-RAY DIFFRACTIONf_plane_restr0.0041625
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.8842-2.98730.37551250.34392390X-RAY DIFFRACTION91
2.9873-3.10680.34891370.29852605X-RAY DIFFRACTION99
3.1068-3.24820.37391340.27972590X-RAY DIFFRACTION99
3.2482-3.41940.30571350.24882586X-RAY DIFFRACTION99
3.4194-3.63360.291370.22732600X-RAY DIFFRACTION99
3.6336-3.9140.25121370.20742599X-RAY DIFFRACTION100
3.914-4.30770.22261380.18452608X-RAY DIFFRACTION100
4.3077-4.93060.19081360.16862591X-RAY DIFFRACTION99
4.9306-6.21010.22171400.19812647X-RAY DIFFRACTION100
6.2101-49.29440.19881390.18832628X-RAY DIFFRACTION99

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