The cryo-EM structure of thePlasmodium falciparum20S proteasome and its use in the fight against malaria

Li, H., Bogyo, M. and da Fonseca, P. C.A. (2016) The cryo-EM structure of thePlasmodium falciparum20S proteasome and its use in the fight against malaria. FEBS Journal, 283(23), pp. 4238-4243. (doi: 10.1111/febs.13780) (PMID:27286897) (PMCID:PMC5140733)

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Abstract

Plasmodium falciparum is the parasite responsible for the most severe form of malaria. Its increasing resistance to existing antimalarials represents a major threat to human health and urges the development of new therapeutic strategies to fight malaria. The proteasome is a protease complex essential in all eukaryotes. Accordingly, inhibition of the Plasmodium 20S proteasome is highly toxic for the parasite at all of its infective and developmental stages. Proteasome inhibitors have antimalarial potential both as curative and transmission blocking agents, but in order to have therapeutic application, they must specifically target the Plasmodium proteasome and not its human counterpart. X‐ray crystallography has been widely used to determine structures of yeast and mammalian 20S proteasomes with ligands. However, crystallisation of the Plasmodium proteasome is challenging, as only small quantities of the complex can be directly purified from the parasite. Furthermore, most X‐ray structures of proteasome–inhibitor complexes require soaking of crystals with high concentrations of ligand, thus preventing analysis of inhibitor subunit specificity. Instead we chose to determine the Plasmodium falciparum 20S proteasome structure, in the presence of a new rationally designed parasite‐specific inhibitor, by high‐resolution electron cryo‐microscopy and single particle analysis. The resulting map, at a resolution of about 3.6 Å, allows a direct molecular analysis of inhibitor/enzyme interactions. Here we present an overview of this structure, and how it provides valuable information that can be used to assist in the design of improved proteasome inhibitors with the potential to be developed as next‐generation antimalarial drugs.

Item Type:Articles
Additional Information:This work was supported by Medical Research Council grant MC_UP_1201/5 to P.C.A.dF., the National Institutes of Health grants R01AI078947 and R01EB05011 to M.B. and a NSS‐PhD scholarship from the Agency for Science, Technology and Research (A*STAR) Singapore to HL.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:da Fonseca, Professor Paula
Authors: Li, H., Bogyo, M., and da Fonseca, P. C.A.
College/School:College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
Journal Name:FEBS Journal
Publisher:Wiley
ISSN:1742-464X
ISSN (Online):1742-4658
Published Online:11 June 2016

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