RGD Reference Report - Crystal structures of rat thymidylate synthase inhibited by Tomudex, a potent anticancer drug. - Rat Genome Database

Send us a Message



Submit Data |  Help |  Video Tutorials |  News |  Publications |  Download |  REST API |  Citing RGD |  Contact   

Crystal structures of rat thymidylate synthase inhibited by Tomudex, a potent anticancer drug.

Authors: Sotelo-Mundo, RR  Ciesla, J  Dzik, JM  Rode, W  Maley, F  Maley, GF  Hardy, LW  Montfort, WR 
Citation: Sotelo-Mundo RR, etal., Biochemistry 1999 Jan 19;38(3):1087-94.
RGD ID: 1545055
Pubmed: PMID:9894005   (View Abstract at PubMed)
DOI: DOI:10.1021/bi981881d   (Journal Full-text)

Two crystal structures of rat thymidylate synthase (TS) complexed with dUMP and the anticancer drug Tomudex (ZD1694) have been determined to resolutions of 3.3 and 2.6 A. Tomudex is one of several new antifolates targeted to TS and the first to be approved for clinical use. The structures represent the first views of any mammalian TS bound to ligands and suggest that the rat protein undergoes a ligand-induced conformational change similar to that of the Escherichia coli protein. Surprisingly, Tomudex does not induce the "closed" conformation in rat TS that is seen on binding to E. coli TS, resulting in inhibitor atoms that differ in position by more than 1.5 A. Several species-specific differences in sequence may be the reason for this. Phe 74 shifts to a new position in the rat complex and is in van der Waals contact with the inhibitor, while in the E. coli protein the equivalent amino acid (His 51) hydrogen bonds to the glutamate portion of the inhibitor. Amino acids Arg 101, Asn 106, and Met 305 make no contacts with the inhibitor in the open conformation, unlike the equivalent residues in the E. coli protein (Thr 78, Trp 83, and Val 262). dUMP binding is similar in both proteins, except that there is no covalent adduct to the active site cysteine (Cys 189) in the rat structures. Two insertions in the rat protein are clearly seen, but the N-termini (residues 1-20) and C-termini (residues 301-307) are disordered in both crystal forms.



Gene-Chemical Interaction Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
TYMSHumanTOMUDEX affects bindingISOTyms (Rattus norvegicus)Tomudex binds to Tyms proteinRGD 
TymsRatTOMUDEX affects bindingEXP Tomudex binds to Tyms proteinRGD 
TymsMouseTOMUDEX affects bindingISOTyms (Rattus norvegicus)Tomudex binds to Tyms proteinRGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
TymsRatdTMP biosynthetic process  IDA  RGD 

Molecular Function

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
TymsRatheterocyclic compound binding  IPITOMUDEX RGD 
TymsRatprotein homodimerization activity  IDA  RGD 
TymsRatthymidylate synthase activity  IDA  RGD 

Molecular Pathway Annotations    Click to see Annotation Detail View

RGD Manual Annotations


  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
TYMSHumanfolate mediated one-carbon metabolic pathway   ISS  RGD 
TymsRatfolate mediated one-carbon metabolic pathway   IDA  RGD 
TYMSHumanfolate metabolic pathway  ISS  RGD 
TymsRatfolate metabolic pathway  IDA  RGD 
TYMSHumanpyrimidine metabolic pathway  ISS  RGD 
TymsRatpyrimidine metabolic pathway  IDA  RGD 
Objects Annotated

Genes (Rattus norvegicus)
Tyms  (thymidylate synthetase)

Genes (Mus musculus)
Tyms  (thymidylate synthase)

Genes (Homo sapiens)
TYMS  (thymidylate synthetase)


Additional Information