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X‐ray crystal structures of an orally available aminopeptidase inhibitor, T osedostat, bound to anti‐malarial drug targets P f A ‐ M 1 and P f A ‐ M 17
Author(s) -
Drinkwater Nyssa,
Bamert Rebecca S.,
Sivaraman Komagal Kannan,
Paiardini Alessandro,
McGowan Sheena
Publication year - 2015
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.24771
Subject(s) - drug , plasmodium falciparum , enzyme , aminopeptidase , malaria , chemistry , binding site , pharmacology , stereochemistry , biology , biochemistry , immunology , amino acid , leucine
New anti‐malarial treatments are desperately required to face the spread of drug resistant parasites. Inhibition of metalloaminopeptidases, Pf A‐M1 and Pf A‐M17, is a validated therapeutic strategy for treatment of Plasmodium falciparum malaria. Here, we describe the crystal structures of Pf A‐M1 and Pf A‐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 Pf A‐M1 and Pf A‐M17. These findings will be valuable for the continued development of selective inhibitors of Pf A‐M1 and Pf A‐M17. Proteins 2015; 83:789–795. © 2015 Wiley Periodicals, Inc.