Structural basis for binding and selectivity of antimalarial and anticancer ethylenediamine inhibitors to protein farnesyltransferase.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Hast, MA; Fletcher, S; Cummings, CG; Pusateri, EE; Blaskovich, MA; Rivas, K; Gelb, MH; Van Voorhis, WC; Sebti, SM; Hamilton, AD; Beese, LS

Published Date

  • February 27, 2009

Published In

Volume / Issue

  • 16 / 2

Start / End Page

  • 181 - 192

PubMed ID

  • 19246009

Pubmed Central ID

  • 19246009

Electronic International Standard Serial Number (EISSN)

  • 1879-1301

Digital Object Identifier (DOI)

  • 10.1016/j.chembiol.2009.01.014

Language

  • eng

Conference Location

  • United States