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J. Biol. Chem., Vol. 281, Issue 9, 5821-5828, March 3, 2006

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The Structure of Leishmania mexicana ICP Provides Evidence for Convergent Evolution of Cysteine Peptidase Inhibitors^*

Brian O. Smith¹, Nichola C. Picken, Gareth D. Westrop, Krystyna Bromek, Jeremy C. Mottram^¶, and Graham H. Coombs^¶

From the Divisions of Biochemistry and Molecular Biology, Infection and Immunity and the ^¶Wellcome Centre for Molecular Parasitology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom

Clan CA, family C1 cysteine peptidases (CPs) are important virulence factors and drug targets in parasites that cause neglected diseases. Natural CP inhibitors of the I42 family, known as ICP, occur in some protozoa and bacterial pathogens but are absent from metazoa. They are active against both parasite and mammalian CPs, despite having no sequence similarity with other classes of CP inhibitor. Recent data suggest that Leishmania mexicana ICP plays an important role in host-parasite interactions. We have now solved the structure of ICP from L. mexicana by NMR and shown that it adopts a type of immunoglobulin-like fold not previously reported in lower eukaryotes or bacteria. The structure places three loops containing highly conserved residues at one end of the molecule, one loop being highly mobile. Interaction studies with CPs confirm the importance of these loops for the interaction between ICP and CPs and suggest the mechanism of inhibition. Structure-guided mutagenesis of ICP has revealed that residues in the mobile loop are critical for CP inhibition. Data-driven docking models support the importance of the loops in the ICP-CP interaction. This study provides structural evidence for the convergent evolution from an immunoglobulin fold of CP inhibitors with a cystatin-like mechanism.

Received for publication, October 5, 2005 , and in revised form, November 29, 2005.

The amino acid sequence of this protein can be accessed through NCBI Protein Database under NCBI accession number CAD68975 [GenBank] .

The atomic coordinates and structure factors (code 2c34) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by a grant (074875/2/04/2) from the Wellcome Trust. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Joseph Black Bldg., Glasgow G12 8QQ, UK. Tel.: 44-141-330-5167; Fax: 44-141-330-8640; E-mail: b.smith{at}bio.gla.ac.uk.

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				K. Bryson, S. Besteiro, H. A. McGachy, G. H. Coombs, J. C. Mottram, and J. Alexander Overexpression of the Natural Inhibitor of Cysteine Peptidases in Leishmania mexicana Leads to Reduced Virulence and a Th1 Response Infect. Immun., July 1, 2009; 77(7): 2971 - 2978. [Abstract] [Full Text] [PDF]