Structural basis for binding and selectivity of antimalarial and anticancer ethylenediamine inhibitors to protein farnesyltransferase.
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.
- SourceAvailable from: pbworks.com[show abstract] [hide abstract]
ABSTRACT: More than 100 proteins necessary for eukaryotic cell growth, differentiation, and morphology require posttranslational modification by the covalent attachment of an isoprenoid lipid (prenylation). Prenylated proteins include members of the Ras, Rab, and Rho families, lamins, CENPE and CENPF, and the gamma subunit of many small heterotrimeric G proteins. This modification is catalyzed by the protein prenyltransferases: protein farnesyltransferase (FTase), protein geranylgeranyltransferase type I (GGTase-I), and GGTase-II (or RabGGTase). In this review, we examine the structural biology of FTase and GGTase-I (the CaaX prenyltransferases) to establish a framework for understanding the molecular basis of substrate specificity and mechanism. These enzymes have been identified in a number of species, including mammals, fungi, plants, and protists. Prenyltransferase structures include complexes that represent the major steps along the reaction path, as well as a number of complexes with clinically relevant inhibitors. Such complexes may assist in the design of inhibitors that could lead to treatments for cancer, viral infection, and a number of deadly parasitic diseases.The Journal of Lipid Research 05/2006; 47(4):681-99. · 4.39 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: A series of protein farnesyltransferase inhibitor ester prodrugs of FTI-2148 (17) were synthesized in order to evaluate the effects of ester structure modification on antimalarial activity and for further development of a farnesyltransferase inhibitor with in vivo activity. Evaluation against P. falciparum in red blood cells showed that all the investigated esters exhibited significant antimalarial activity, with the benzyl ester 16 showing the best inhibition (ED50=150 nM). Additionally, compound 16 displayed in vivo activity and was found to suppress parasitemia by 46.1% at a dose of 50 mg kg(-1) day(-1) against Plasmodium berghei in mice. The enhanced inhibition potency of the esters is consistent with improved cell membrane permeability compared to that of the free acid. The results of this study suggest that protein farnesyltransferase is a valid antimalarial drug target and that the antimalarial activity of these compounds derives from a balance between the hydrophobic character and the size and conformation of the ester moiety.Bioorganic & Medicinal Chemistry 01/2005; 12(24):6517-26. · 2.90 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Many signal transduction proteins that control growth, differentiation, and transformation, including Ras GTPase family members, require the covalent attachment of a lipid group by protein farnesyltransferase (FTase) or protein geranylgeranyltransferase type-I (GGTase-I) for proper function and for the transforming activity of oncogenic mutants. FTase inhibitors are a new class of potential cancer therapeutics under evaluation in human clinical trials. Here, we present crystal structures of the clinical candidate L-778,123 complexed with mammalian FTase and complexed with the related GGTase-I enzyme. Although FTase and GGTase-I have very similar active sites, L-778,123 adopts different binding modes in the two enzymes; in FTase, L-778,123 is competitive with the protein substrate, whereas in GGTase-I, L-778,123 is competitive with the lipid substrate and inhibitor binding is synergized by tetrahedral anions. A comparison of these complexes reveals that small differences in protein structure can dramatically affect inhibitor binding and selectivity. These structures should facilitate the design of more specific inhibitors toward FTase or GGTase-I. Finally, the binding of a drug and anion together could be applicable for developing new classes of inhibitors.Biochemistry 08/2004; 43(28):9000-8. · 3.38 Impact Factor