Palestra – Prof. Dr. Walid A. Houry
| Título: “Insights into the Mechanism of Function of the Protein Unfolding and Degradation System ClpXP“
Prof. Dr. Walid A. Houry Medical Sciences Building, Department of Biochemistry, University of Toronto – Canada Data: 17 de novembro de 2014 Horário: 16 h . |
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| Resumo da palestra:.ClpP is a cylindrical tetradecameric serine protease whose activity is regulated by the unfoldase ATP-dependent chaperones of the AAA+ superfamily such as ClpX, ClpA, and ClpC. The chaperones act to select substrate proteins, unfold them, and then thread them into the ClpP cylinder for degradation. ClpP on its own can only degrade small peptides. Structural and functional studies from my group have elucidated the mechanism of function of the ClpXP chaperone-protease system. These studies highlighted the importance of protein dynamics in this system. Furthermore, we uncovered the presence of functional cooperativity between ClpXP and some folding chaperones. Recently, we used ClpP as a target in a high-throughput screen for compounds which activate the protease and allow it to degrade larger proteins, hence, abolishing the specificity arising from the ATP-dependent chaperones. Our screen resulted in five structurally distinct compounds, which we designated as Activators of Self-Compartmentalizing Proteases 1 to 5 (ACP1 to 5). The compounds were found to stabilize the ClpP double ring structure. The ACP1 chemical structure was considered to have drug-like characteristics and was further optimized to give analogs with bactericidal activity. Hence, the ACPs represent new classes of compounds that can activate ClpP and that can be developed as potential novel antibiotics. Progress in our studies on the E. coli and P. falciparum Clp systems will be presented. | 
Divulgação
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