PDBsum entry 1tsl

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protein ligands links
Methyltransferase PDB id
Protein chain
316 a.a. *
Waters ×313
* Residue conservation analysis
PDB id:
Name: Methyltransferase
Title: L. Casei thymidylate synthase with species specific inhibito
Structure: Thymidylate synthase. Chain: a. Synonym: ts, thymidylate synthetase. Engineered: yes
Source: Lactobacillus casei. Organism_taxid: 1582. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Dimer (from PDB file)
2.50Å     R-factor:   0.163     R-free:   0.251
Authors: T.J.Stout,R.M.Stroud
Key ref:
T.J.Stout et al. (1999). Structure-based design of inhibitors specific for bacterial thymidylate synthase. Biochemistry, 38, 1607-1617. PubMed id: 9931028 DOI: 10.1021/bi9815896
12-Jun-97     Release date:   17-Jun-98    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P00469  (TYSY_LACCA) -  Thymidylate synthase
316 a.a.
316 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.  - Thymidylate synthase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

Folate Coenzymes
      Reaction: 5,10-methylenetetrahydrofolate + dUMP = dihydrofolate + dTMP
+ dUMP
= dihydrofolate
+ dTMP
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cytoplasm   1 term 
  Biological process     methylation   4 terms 
  Biochemical function     transferase activity     3 terms  


DOI no: 10.1021/bi9815896 Biochemistry 38:1607-1617 (1999)
PubMed id: 9931028  
Structure-based design of inhibitors specific for bacterial thymidylate synthase.
T.J.Stout, D.Tondi, M.Rinaldi, D.Barlocco, P.Pecorari, D.V.Santi, I.D.Kuntz, R.M.Stroud, B.K.Shoichet, M.P.Costi.
Thymidylate synthase is an attractive target for antiproliferative drug design because of its key role in the synthesis of DNA. As such, the enzyme has been widely targeted for anticancer applications. In principle, TS should also be a good target for drugs used to fight infectious disease. In practice, TS is highly conserved across species, and it has proven to be difficult to develop inhibitors that are selective for microbial TS enzymes over the human enzyme. Using the structure of TS from Lactobacillus casei in complex with the nonsubstrate analogue phenolphthalein, inhibitors were designed to take advantage of features of the bacterial enzyme that differ from those of the human enzyme. Upon synthesis and testing, these inhibitors were found to be up to 40-fold selective for the bacterial enzyme over the human enzyme. The crystal structures of two of these inhibitors in complex with TS suggested the design of further compounds. Subsequent synthesis and testing showed that these second-round compounds inhibit the bacterial enzyme at sub-micromolar concentrations, while the human enzyme was not inhibited at detectable levels (selectivities of 100-1000-fold or greater). Although these inhibitors share chemical similarities, X-ray crystal structures reveal that the analogues bind to the enzyme in substantially different orientations. Site-directed mutagenesis experiments suggest that the individual inhibitors may adopt multiple configurations in their complexes with TS.

Literature references that cite this PDB file's key reference

  PubMed id Reference
  20034113 C.D.Andersson, B.Y.Chen, and A.Linusson (2010).
Mapping of ligand-binding cavities in proteins.
  Proteins, 78, 1408-1422.  
19368882 D.L.Mobley, and K.A.Dill (2009).
Binding of small-molecule ligands to proteins: "what you see" is not always "what you get".
  Structure, 17, 489-498.  
18403248 A.A.Arvizu-Flores, R.Sugich-Miranda, R.Arreola, K.D.Garcia-Orozco, E.F.Velazquez-Contreras, W.R.Montfort, F.Maley, and R.R.Sotelo-Mundo (2008).
Role of an invariant lysine residue in folate binding on Escherichia coli thymidylate synthase: calorimetric and crystallographic analysis of the K48Q mutant.
  Int J Biochem Cell Biol, 40, 2206-2217.
PDB codes: 2vet 2vf0 3b5b
18493582 J.H.Hunter, R.Gujjar, C.K.Pang, and P.K.Rathod (2008).
Kinetics and ligand-binding preferences of Mycobacterium tuberculosis thymidylate synthases, ThyA and ThyX.
  PLoS ONE, 3, e2237.  
18270995 S.Ferrari, V.Losasso, and M.P.Costi (2008).
Sequence-based identification of specific drug target regions in the thymidylate synthase enzyme family.
  ChemMedChem, 3, 392-401.  
17216455 A.Chernyshev, T.Fleischmann, and A.Kohen (2007).
Thymidyl biosynthesis enzymes as antibiotic targets.
  Appl Microbiol Biotechnol, 74, 282-289.  
16075306 A.JarmuĊ‚a, P.Cieplak, and W.R.Montfort (2005).
5,10-Methylene-5,6,7,8-tetrahydrofolate conformational transitions upon binding to thymidylate synthase: molecular mechanics and continuum solvent studies.
  J Comput Aided Mol Des, 19, 123-136.  
16204883 J.S.Finer-Moore, A.C.Anderson, R.H.O'Neil, M.P.Costi, S.Ferrari, J.Krucinski, and R.M.Stroud (2005).
The structure of Cryptococcus neoformans thymidylate synthase suggests strategies for using target dynamics for species-specific inhibition.
  Acta Crystallogr D Biol Crystallogr, 61, 1320-1334.
PDB codes: 2a9w 2aaz
15935511 M.Kilstrup, K.Hammer, P.Ruhdal Jensen, and J.Martinussen (2005).
Nucleotide metabolism and its control in lactic acid bacteria.
  FEMS Microbiol Rev, 29, 555-590.  
14700626 S.Ferrari, P.M.Costi, and R.C.Wade (2003).
Inhibitor specificity via protein dynamics: insights from the design of antibacterial agents targeted against thymidylate synthase.
  Chem Biol, 10, 1183-1193.  
12838268 S.J.Teague (2003).
Implications of protein flexibility for drug discovery.
  Nat Rev Drug Discov, 2, 527-541.  
11358692 A.C.Anderson, R.H.O'Neil, T.S.Surti, and R.M.Stroud (2001).
Approaches to solving the rigid receptor problem by identifying a minimal set of flexible residues during ligand docking.
  Chem Biol, 8, 445-457.
PDB code: 1f28
11316879 R.Almog, C.A.Waddling, F.Maley, G.F.Maley, and P.Van Roey (2001).
Crystal structure of a deletion mutant of human thymidylate synthase Delta (7-29) and its ternary complex with Tomudex and dUMP.
  Protein Sci, 10, 988-996.
PDB codes: 1hzw 1i00
11590022 T.A.Fritz, D.Tondi, J.S.Finer-Moore, M.P.Costi, and R.M.Stroud (2001).
Predicting and harnessing protein flexibility in the design of species-specific inhibitors of thymidylate synthase.
  Chem Biol, 8, 981-995.
PDB code: 1jg0
10944209 D.A.Erlanson, A.C.Braisted, D.R.Raphael, M.Randal, R.M.Stroud, E.M.Gordon, and J.A.Wells (2000).
Site-directed ligand discovery.
  Proc Natl Acad Sci U S A, 97, 9367-9372.
PDB codes: 1f4b 1f4c 1f4d 1f4e 1f4f 1f4g
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.