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J Med Chem. 2009 Feb 12;52(3):852-7. doi: 10.1021/jm8013663.

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

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Department of Cellular and Molecular Pharmacology and Department of Pathology, University of California, San Francisco, California 94158, USA.


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.

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