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: Iain D Kerr, Ji H Lee, Kailash C Pandey, Amanda Harrison, Mohammed Sajid, Philip J Rosenthal, Linda S Brinen
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 52 Issue 3 Pg. 852-7 (Feb 12 2009) ISSN: 1520-4804 [Electronic] United States
• PMID: 19128015 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Cysteine Proteinase Inhibitors
• Leupeptins
• Cysteine Endopeptidases
• falcipain 2
• falcipain 3
• leupeptin

Topics

• Animals
• Catalytic Domain
• Crystallization
• Crystallography, X-Ray
• Cysteine Endopeptidases (chemistry)
• Cysteine Proteinase Inhibitors (chemistry)
• Kinetics
• Leupeptins (chemistry)
• Models, Molecular
• Plasmodium falciparum (enzymology)
• Substrate Specificity