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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.

SUBMITTER: Kerr ID

PROVIDER: S-EPMC2651692 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Structures of falcipain-2 and falcipain-3 bound to small molecule inhibitors: implications for substrate specificity.

Kerr Iain D ID Lee Ji H JH Pandey Kailash C KC Harrison Amanda A Sajid Mohammed M Rosenthal Philip J PJ Brinen Linda S LS

Journal of medicinal chemistry 20090201 3

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 structur ...[more]

PMID: 19128015

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