Structural Basis for Binding and Selectivity of Antimalarial and Anticancer Ethylenediamine Inhibitors to Protein Farnesyltransferase

Michael A. Hast, Steven Fletcher, Christopher G. Cummings, Erin E. Pusateri, Michelle A. Blaskovich, Kasey Rivas, Michael H. Gelb, Wesley C. Van Voorhis, Said M. Sebti, Andrew D. Hamilton, Lorena S. Beese

Research output: Contribution to journalArticlepeer-review

Abstract

Protein farnesyltransferase (FTase) catalyzes an essential posttranslational lipid modification of more than 60 proteins involved in intracellular signal transduction networks. FTase inhibitors have emerged as a significant target for development of anticancer therapeutics and, more recently, for the treatment of parasitic diseases caused by protozoan pathogens, including malaria (Plasmodium falciparum). We present the X-ray crystallographic structures of complexes of mammalian FTase with five inhibitors based on an ethylenediamine scaffold, two of which exhibit over 1000-fold selective inhibition of P. falciparum FTase. These structures reveal the dominant determinants in both the inhibitor and enzyme that control binding and selectivity. Comparison to a homology model constructed for the P. falciparum FTase suggests opportunities for further improving selectivity of a new generation of antimalarial inhibitors.

Original languageEnglish (US)
Pages (from-to)181-192
Number of pages12
JournalChemistry and Biology
Volume16
Issue number2
DOIs
StatePublished - Feb 27 2009

Keywords

  • CHEMBIO
  • MICROBIO
  • PROTEINS

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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