title: X-ray crystal structures of an orally available aminopeptidase inhibitor, Tosedostat, bound to anti-malarial drug targets PfA-M1 and PfA-M17.
abstract: New anti-malarial treatments are desperately required to face the spread of drug resistant parasites. Inhibition of metalloaminopeptidases, PfA-M1 and PfA-M17, is a validated therapeutic strategy for treatment of Plasmodium falciparum malaria. Here, we describe the crystal structures of PfA-M1 and PfA-M17 bound to chemotherapeutic agent Tosedostat. The inhibitor occupies the enzymes' putative product egress channels in addition to the substrate binding pockets; however, adopts different binding poses when bound to PfA-M1 and PfA-M17. These findings will be valuable for the continued development of selective inhibitors of PfA-M1 and PfA-M17.
authors: Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria, 3800, Australia.
authors: Nyssa
authors: N
authors: Drinkwater
authors: Rebecca S
authors: RS
authors: Bamert
authors: Komagal Kannan
authors: KK
authors: Sivaraman
authors: Alessandro
authors: A
authors: Paiardini
authors: Sheena
authors: S
authors: McGowan
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors; D000962:Antimalarials / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D005998:Glycine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D006877:Hydroxamic Acids / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D010963:Plasmodium falciparum; D015800:Protozoan Proteins / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000962:Antimalarials; D006877:Hydroxamic Acids; D015800:Protozoan Proteins; D000626:Aminopeptidases; C531970:tosedostat; D005998:Glycine
keywords: Plasmodium falciparum; Tosedostat; inhibitors; malaria; protease; structural biology