The crystal structure of thymidylate synthase from Pneumocystis carinii reveals a fungal insert important for drug design

Amy C. Anderson, Kathy M. Perry, Douglas M. Freymann, Robert M. Stroud*

*Corresponding author for this work

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Thymidylate synthase from Pneumocystis carinii (PcTS) is an especially important drug target, since P. carinii is a fungus that causes opportunistic pneumonia infections in immune-compromised patients and is among the leading causes of death of AIDS patients. Thymidylate synthase (TS) is the sole enzyme responsible for the de novo production of deoxythymidine monophosphate and hence is crucial for DNA replication in every organism. Inhibitors selective for P. carinii TS over human TS would be greatly beneficial in combating this disease. The crystal structure of TS from P. carinii bound to its substrate, dUMP, and a cofactor mimic, CB3717, was determined to 2.6 A resolution. A comparison with other species of TS shows that the volume of the closed PcTS active-site is 20% larger than that of five other TS closed active-sites. A two-residue proline insert that is strictly conserved among all fungal species of TS, and a novel C-terminal closing interaction involving a P. carinii-specific tyrosine residue are primarily responsible for this increase in volume. The structure suggests several options for designing an inhibitor specific to PcTS and avoiding interactions with human TS. Taking advantage of the residue substitutions of P. carinii TS over human TS enables the design of a selective inhibitor. Additionally, the larger volume of the active-site of PcTS is an important advantage for designing de novo inhibitors that will exclude the human TS active-site through steric hindrance. (C) 2000 Academic Press.

Original languageEnglish (US)
Pages (from-to)645-657
Number of pages13
JournalJournal of Molecular Biology
Volume297
Issue number3
DOIs
StatePublished - Mar 31 2000

Keywords

  • AIDS
  • Anti-fungal
  • Crystal structure
  • Drug design
  • Thymidylate synthase

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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