Structure. 2011 Jul 13;19(7):919-29.

Structural basis for the regulation of cysteine-protease activity by a new class of protease inhibitors in Plasmodium.

Hansen G, Heitmann A, Witt T, Li H, Jiang H, Shen X, Heussler VT, Rennenberg A, Hilgenfeld R.

Source

Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, 23538 Lübeck, Germany.

Abstract

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.

Comment in

Structure. 2011 Jul 13;19(7):901-2.

PMID:: 21742259; [PubMed - indexed for MEDLINE]

Publication Types, MeSH Terms, Substances, Secondary Source ID

Publication Types

Research Support, Non-U.S. Gov't

MeSH Terms

Substances

Secondary Source ID

PDB/3PNR

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Malaria - MedlinePlus Health Information

Supplemental Content

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Structures reported by this article

Structure Of Pbicp-C In Complex With Falcipain-2

PDB: 3PNR

Source: Plasmodium falciparum, Plasmodium berghei

Method: X-Ray Diffraction

Resolution: 2.6 Å

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Structure
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