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PDBsum entry 1tlc
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protein ligands Protein-protein interface(s) links
Methyltransferase PDB id
1tlc

 

 

 

 

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Contents
Protein chains
265 a.a. *
Ligands
DGP ×2
F89 ×2
Waters ×166
* Residue conservation analysis
PDB id:
1tlc
Name: Methyltransferase
Title: Thymidylate synthase complexed with dgmp and folate analog 1843u89
Structure: Thymidylate synthase. Chain: a, b. Engineered: yes
Source: Escherichia coli. Organism_taxid: 562
Biol. unit: Dimer (from PQS)
Resolution:
2.10Å     R-factor:   0.180    
Authors: A.Weichsel,W.R.Montfort,J.Ciesla,F.Maley
Key ref: A.Weichsel et al. (1995). Promotion of purine nucleotide binding to thymidylate synthase by a potent folate analogue inhibitor, 1843U89. Proc Natl Acad Sci U S A, 92, 3493-3497. PubMed id: 7724588 DOI: 10.1073/pnas.92.8.3493
Date:
07-Mar-95     Release date:   03-Jun-95    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P0A884  (TYSY_ECOLI) -  Thymidylate synthase from Escherichia coli (strain K12)
Seq:
Struc: 		264 a.a.
265 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.2.1.1.45  - thymidylate synthase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway: 		Folate Coenzymes
      Reaction: dUMP + (6R)-5,10-methylene-5,6,7,8-tetrahydrofolate = 7,8-dihydrofolate + dTMP
dUMP
Bound ligand (Het Group name = DGP)
matches with 79.17% similarity 		+ (6R)-5,10-methylene-5,6,7,8-tetrahydrofolate
 =
7,8-dihydrofolate
Bound ligand (Het Group name = F89)
matches with 46.81% similarity 		+ dTMP
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    reference    
 
 
DOI no: 10.1073/pnas.92.8.3493 Proc Natl Acad Sci U S A 92:3493-3497 (1995)
PubMed id: 7724588  
 
 
Promotion of purine nucleotide binding to thymidylate synthase by a potent folate analogue inhibitor, 1843U89.
A.Weichsel, W.R.Montfort, J.Cieśla, F.Maley.
 
  ABSTRACT  
 
A folate analogue, 1843U89 (U89), with potential as a chemotherapeutic agent due to its potent and specific inhibition of thymidylate synthase (TS; EC 2.1.1.45), greatly enhances not only the binding of 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP) and dUMP to Escherichia coli TS but also that of dGMP, GMP, dIMP, and IMP. Guanine nucleotide binding was first detected by CD analysis, which revealed a unique spectrum for the TS-dGMP-U89 ternary complex. The quantitative binding of dGMP relative to GMP, FdUMP, and dUMP was determined in the presence and absence of U89 by ultrafiltration analysis, which revealed that although the binding of GMP and dGMP could not be detected in the absence of U89 both were bound in its presence. The Kd for dGMP was about the same as that for dUMP and FdUMP, with binding of the latter two nucleotides being increased by two orders of magnitude by U89. An explanation for the binding of dGMP was provided by x-ray diffraction studies that revealed an extensive stacking interaction between the guanine of dGMP and the benzoquinazoline ring of U89 and hydrogen bonds similar to those involved in dUMP binding. In addition, binding energy was provided through a water molecule that formed hydrogen bonds to both N7 of dGMP and the hydroxyl of Tyr-94. Accommodation of the larger dGMP molecule was accomplished through a distortion of the active site and a shift of the deoxyribose moiety to a new position. These rearrangements also enabled the binding of GMP to occur by creating a pocket for the ribose 2' hydroxyl group, overcoming the normal TS discrimination against nucleotides containing the 2' hydroxyl.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
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
16010590 O.H.Temmink, M.F.Hoogeland, M.Fukushima, and G.J.Peters (2006).
Low folate conditions may enhance the interaction of trifluorothymidine with antifolates in colon cancer cells.
  Cancer Chemother Pharmacol, 57, 171-179.  
9521774 A.P.Lobo, M.G.Nair, L.Changchien, A.Weichsel, W.R.Montfort, and F.Maley (1998).
Mode of action of site-directed irreversible folate analogue inhibitors of thymidylate synthase.
  Biochemistry, 37, 4535-4542.  
9436180 M.P.Costi (1998).
Thymidylate synthase inhibition: a structure-based rationale for drug design.
  Med Res Rev, 18, 21-42.  
9109668 D.C.Hyatt, F.Maley, and W.R.Montfort (1997).
Use of strain in a stereospecific catalytic mechanism: crystal structures of Escherichia coli thymidylate synthase bound to FdUMP and methylenetetrahydrofolate.
  Biochemistry, 36, 4585-4594.
PDB codes: 1tls 1tsn
9100016 H.T.Spencer, J.E.Villafranca, and J.R.Appleman (1997).
Kinetic scheme for thymidylate synthase from Escherichia coli: determination from measurements of ligand binding, primary and secondary isotope effects, and pre-steady-state catalysis.
  Biochemistry, 36, 4212-4222.  
8679643 C.H.Chen, R.A.Davis, and F.Maley (1996).
Thermodynamic stabilization of nucleotide binding to thymidylate synthase by a potent benzoquinazoline folate analogue inhibitor.
  Biochemistry, 35, 8786-8793.  
8805515 T.J.Stout, and R.M.Stroud (1996).
The complex of the anti-cancer therapeutic, BW1843U89, with thymidylate synthase at 2.0 A resolution: implications for a new mode of inhibition.
  Structure, 4, 67-77.
PDB code: 1syn
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.

 

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