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Structural basis for binding and selectivity of antimalarial and anticancer ethylenediamine inhibitors to protein farnesyltransferase.
Title | Structural basis for binding and selectivity of antimalarial and anticancer ethylenediamine inhibitors to protein farnesyltransferase. |
Publication Type | Journal Article |
Year of Publication | 2009 |
Authors | Hast, MA, Fletcher, S, Cummings, CG, Pusateri, EE, Blaskovich, MA, Rivas, K, Gelb, MH, Van Voorhis, WC, Sebti, SM, Hamilton, AD, Beese, LS |
Journal | Chem Biol |
Volume | 16 |
Issue | 2 |
Pagination | 181-92 |
Date Published | 2009 Feb 27 |
ISSN | 1879-1301 |
Keywords | Animals, Antimalarials, Antineoplastic Agents, Cell Line, Tumor, Crystallography, X-Ray, Enzyme Inhibitors, Ethylenediamines, Farnesyltranstransferase, Humans, Plasmodium falciparum, Protein Binding, Protein Conformation, Protozoan Proteins, Rats, Structural Homology, Protein, Structure-Activity Relationship, Substrate Specificity |
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. |
DOI | 10.1016/j.chembiol.2009.01.014 |
Alternate Journal | Chem. Biol. |
PubMed ID | 19246009 |