Structural Basis for Unique Mechanisms of Folding and Hemoglobin Binding by a Malarial Protease.
From: Department of Pathology and the Sandler Center, San Francisco General Hospital, University of California, CA 94143, USA.
Proceedings of the National Academy of Sciences of the United States of America
- Publish Date: Aug 2006
- ISSN: 0027-8424
- Volume: 103
- Issue: 31
- Pages: 11503-8
- Medium: Print
- Language: English
- Citation (JAMA): Wang Stephanie X, Pandey Kailash C, Somoza John R, et al. Structural Basis for Unique Mechanisms of Folding and Hemoglobin Binding by a Malarial Protease.. Proc. Natl. Acad. Sci. U.S.A. Aug 2006;103:11503-8
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.
Mesh Headings (Keywords): Amino Acid Sequence, Animals, Crystallography, X-Ray, Cystatins, Cysteine Endopeptidases, Hemoglobins, Humans, Models, Molecular, Molecular Sequence Data, Plasmodium falciparum, Protein Binding, Protein Folding, Protein Structure, Tertiary, Sequence Alignment, Sequence Homology, Amino Acid
Check for Full Text / PubMed Unique Identifier (PMID): 16864794
This abstract is part of PubMed, a service of the U.S. National Library of Medicine. PubMed includes more than 17 million citations from MEDLINE and other life science journals for biomedical articles. See Copyright and Disclaimers.
Linked medical terms appearing on this page are added by Healia to help readers find more information and are not part of the original PubMed document.
The data herein was last updated on July 8th, 2008 and may not reflect the most current and accurate data available from NLM.