Molecular Architecture of Leishmania Ef-1alpha Reveals a Novel Site That May Modulate Protein Translation: a Possible Target for Drug Development.
From: Department of Medicine (Division of Infectious Diseases), University of British Columbia, Faculties of Medicine and Science, 2733 Heather Street, Heather Pavilion East, Room 452-D, Vancouver, BC, Canada V5Z 3J5.
Biochemical and biophysical research communications
- Publish Date: May 2007
- ISSN: 0006-291X
- Volume: 356
- Issue: 4
- Pages: 886-92
- Medium: Print
- Language: English
- Citation (JAMA): Lopez Martin, Cherkasov Artem, Nandan Devki, et al. Molecular Architecture of Leishmania Ef-1alpha Reveals a Novel Site That May Modulate Protein Translation: a Possible Target for Drug Development.. Biochem. Biophys. Res. Commun. May 2007;356:886-92
Abstract
Elongation factor-1alpha plays an essential role in eukaryotic protein biosynthesis. Recently, we have shown by protein structure modeling the presence of a hairpin-loop of 12 amino acids in mammalian EF-1alpha that is absent in the leishmania homologue [D. Nandan, A. Cherkasov, R. Sabouti, T. Yi, N.E. Reiner, Molecular cloning, biochemical and structural analysis of elongation factor-1 alpha from Leishmania donovani: comparison with the mammalian homologue, Biochem. Biophys. Res. Commun. 302 (2003) 646-652]. As a consequence of this deletion, an exposed region is available on the main body of leishmania EF-1alpha. Here we report the generation of an anti-EF-1alpha antibody (DN-3) which bound selectively to the exposed region of leishmania EF-1alpha, with no reactivity with human EF-1alpha. In a leishmania cell-free protein translation system, DN-3 substantially inhibited protein translation. A similar inhibitory effect was observed when a specific peptide based on the exposed region was used in the cell-free protein translation assay. The application of structure-based in silico methods to identify potential ligands to target the exposed region identified a small molecule that selectively attenuated in vitro translation using leishmania extracts. Moreover, this small molecule showed selective suppressive effect on multiplication of leishmania in culture. Taken together, these findings identify a novel, exposed region in leishmania EF-1alpha that may be involved in protein synthesis and a potential site for drug targeting.
Mesh Headings (Keywords): Amino Acid Sequence, Animals, Binding Sites, Cells, Cultured, Drug Delivery Systems, Drug Design, Leishmania, Molecular Sequence Data, Peptide Elongation Factor 1, Protein Binding, Protein Biosynthesis, Structure-Activity Relationship
Check for Full Text / PubMed Unique Identifier (PMID): 17397800
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