Structures of falcipain-2 and falcipain-3 bound to small molecule inhibitors: implications for substrate specificity.
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.
Kerr
Iain D
ID
Department of Cellular and Molecular Pharmacology and Department of Pathology, University of California, San Francisco, California 94158, USA.
Lee
Ji H
JH
Pandey
Kailash C
KC
Harrison
Amanda
A
Sajid
Mohammed
M
Rosenthal
Philip J
PJ
Brinen
Linda S
LS
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
D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D003546:Cysteine Endopeptidases; C416224:falcipain 2; C443101:falcipain 3; C032854:leupeptin