Structural Basis for the Regulation of Cysteine-Protease Activity by a New Class of Protease Inhibitors in Plasmodium

Plasmodium cysteine proteases are essential for host-cell invasion and egress, hemoglobin degradation, and intracellular development of the parasite. The temporal, site-specific regulation of cysteine-protease activity is a prerequisite for survival and propagation of Plasmodium. Recently, a new fam...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Structure (London) 2011-07, Vol.19 (7), p.919-929
Hauptverfasser: Hansen, Guido, Heitmann, Anna, Witt, Tina, Li, Honglin, Jiang, Hualiang, Shen, Xu, Heussler, Volker T., Rennenberg, Annika, Hilgenfeld, Rolf
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung:Plasmodium cysteine proteases are essential for host-cell invasion and egress, hemoglobin degradation, and intracellular development of the parasite. The temporal, site-specific regulation of cysteine-protease activity is a prerequisite for survival and propagation of Plasmodium. Recently, a new family of inhibitors of cysteine proteases (ICPs) with homologs in at least eight Plasmodium species has been identified. Here, we report the 2.6 Å X-ray crystal structure of the C-terminal, inhibitory domain of ICP from P. berghei (PbICP-C) in a 1:1 complex with falcipain-2, an important hemoglobinase of Plasmodium. The structure establishes Plasmodium ICP as a member of the I42 class of chagasin-like protease inhibitors but with large insertions and differences in the binding mode relative to other family members. Furthermore, the PbICP-C structure explains why host-cell cathepsin B-like proteases and, most likely, also the protease-like domain of Plasmodium SERA5 (serine-repeat antigen 5) are no targets for ICP. ► Structure of ICP-C from P. berghei in complex with falcipain-2 ► The inhibitor interacts with the protease via four loops ► Mutagenic analysis defines specificity determinants of the interaction ► The C-terminal domain of Plasmodium ICP is sufficient for full protease inhibition
ISSN:0969-2126
1878-4186
DOI:10.1016/j.str.2011.03.025