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

Journal Article · Fri Mar 20 04:00:00 EDT 2009 · Chem. Biol.

DOI:https://doi.org/10.1016/j.chembiol.2009.01.014· OSTI ID:1018554

Hast, Michael A; Fletcher, Steven; Cummings, Christopher G; Pusateri, Erin E; Blaskovich, Michelle A; Rivas, Kasey; Gelb, Michael H; Voorhis, Wesley C Van; Sebti, Said M; Hamilton, Andrew D; Beese, Lorena S ^[1]

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1. (Yale)

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.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: USDOE Office of Science (SC)
• OSTI ID: 1018554
• Journal Information: Chem. Biol., Journal Name: Chem. Biol. Journal Issue: (2) ; 02, 2009 Vol. 16; ISSN 1074-5521
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
ENZYMES
LIPIDS
MALARIA
MODIFICATIONS
PARASITIC DISEASES
PATHOGENS
PLASMODIUM
PROTEINS
TARGETS