title: Structures of falcipain-2 and falcipain-3 bound to small molecule inhibitors: implications for substrate specificity.
abstract: Falcipain-2 and falcipain-3 are critical hemoglobinases of Plasmodium falciparum, the most virulent human malaria parasite. We have determined the 2.9 A crystal structure of falcipain-2 in complex with the epoxysuccinate E64 and the 2.5 A crystal structure of falcipain-3 in complex with the aldehyde leupeptin. These complexes represent the first crystal structures of plasmodial cysteine proteases with small molecule inhibitors and the first reported crystal structure of falcipain-3. Our structural analyses indicate that the relative shape and flexibility of the S2 pocket are affected by a number of discrete amino acid substitutions. The cumulative effect of subtle differences, including those at "gatekeeper" positions, may explain the observed kinetic differences between these two closely related enzymes.
authors.affiliation: Department of Cellular and Molecular Pharmacology and Department of Pathology, University of California, San Francisco, California 94158, USA.
authors.forename: Iain D
authors.initials: ID
authors.lastname: Kerr
authors.forename: Ji H
authors.initials: JH
authors.lastname: Lee
authors.forename: Kailash C
authors.initials: KC
authors.lastname: Pandey
authors.forename: Amanda
authors.initials: A
authors.lastname: Harrison
authors.forename: Mohammed
authors.initials: M
authors.lastname: Sajid
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.forename: Linda S
authors.initials: LS
authors.lastname: Brinen
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D003460:Crystallization; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000737:chemistry*; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry*; D007700:Kinetics; D007976:Leupeptins / Q000737:chemistry*; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000201:enzymology; D013379:Substrate Specificity
chemical_list: D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D003546:Cysteine Endopeptidases; C416224:falcipain 2; C443101:falcipain 3; C032854:leupeptin