title: 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.
authors.affiliation: Department of Biochemistry, Duke University Medical Center, Box 3711, Durham, NC 27710, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Hast
authors.forename: Steven
authors.initials: S
authors.lastname: Fletcher
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Cummings
authors.forename: Erin E
authors.initials: EE
authors.lastname: Pusateri
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Blaskovich
authors.forename: Kasey
authors.initials: K
authors.lastname: Rivas
authors.forename: Michael H
authors.initials: MH
authors.lastname: Gelb
authors.forename: Wesley C
authors.initials: WC
authors.lastname: Van Voorhis
authors.forename: Said M
authors.initials: SM
authors.lastname: Sebti
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Hamilton
authors.forename: Lorena S
authors.initials: LS
authors.lastname: Beese
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D005029:Ethylenediamines / Q000737:chemistry; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D010963:Plasmodium falciparum / Q000201:enzymology; D011485:Protein Binding; D011487:Protein Conformation; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D000962:Antimalarials; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005029:Ethylenediamines; D015800:Protozoan Proteins; C031234:ethylenediamine; D051231:Farnesyltranstransferase