1YVB

the Plasmodium falciparum Cysteine Protease Falcipain-2

Summary for 1YVB

• Entry DOI: 10.2210/pdb1yvb/pdb
• Related: 1AIM 1ATK 1PE6
• Descriptor: falcipain 2, Cystatin, GLYCEROL, ... (4 entities in total)
• Functional Keywords: cysteine protease-inhibitor complex, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Plasmodium falciparum; More
• Cellular location: Secreted: P01038
• Total number of polymer chains: 2
• Total formula weight: 39867.14

Authors

Wang, S.X. (deposition date: 2005-02-15, release date: 2006-03-28, Last modification date: 2023-08-23)

Primary citation

Wang, S.X.,Pandey, K.C.,Somoza, J.R.,Sijwali, P.S.,Kortemme, T.,Brinen, L.S.,Fletterick, R.J.,Rosenthal, P.J.,McKerrow, J.H.
Structural basis for unique mechanisms of folding and hemoglobin binding by a malarial protease.
Proc.Natl.Acad.Sci.Usa, 103:11503-11508, 2006

PubMed Abstract: Falcipain-2 (FP2), the major cysteine protease of the human malaria parasite Plasmodium falciparum, is a hemoglobinase and promising drug target. Here we report the crystal structure of FP2 in complex with a protease inhibitor, cystatin. The FP2 structure reveals two previously undescribed cysteine protease structural motifs, designated FP2(nose) and FP2(arm), in addition to details of the active site that will help focus inhibitor design. Unlike most cysteine proteases, FP2 does not require a prodomain but only the short FP2(nose) motif to correctly fold and gain catalytic activity. Our structure and mutagenesis data suggest a molecular basis for this unique mechanism by highlighting the functional role of two Tyr within FP2(nose) and a conserved Glu outside this motif. The FP2(arm) motif is required for hemoglobinase activity. The structure reveals topographic features and a negative charge cluster surrounding FP2(arm) that suggest it may serve as an exo-site for hemoglobin binding. Motifs similar to FP2(nose) and FP2(arm) are found only in related plasmodial proteases, suggesting that they confer malaria-specific functions.

PubMed: 16864794
DOI: 10.1073/pnas.0600489103

Experimental method

X-RAY DIFFRACTION (2.7 Å)