Abstract Paula da Fonseca

Within the scope of "IMpaCT - imaging life from molecules to cells - building knowledge on cryo-electron microscopy methodologies at ITQB NOVA", we would like to invite you to our Seminar:  

Date: October 3 (Tuesday) 

Time:  2.30pm WEST / 3.30pm CEST / 4.30 pm EEST

Expert speaker: Paula da Fonseca, University of Glasgow (UK)

@ ITQB NOVA auditorium & Webinar link

This series of Seminars are part of our strategy to bring to ITQB NOVA world-wide renowned scientists in the field of cryo-EM, sharing with us their vast experience, and helping us to build a network of connections and knowledge within this area.

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IMpaCT CryoEM seminar

Title: Cryo-EM in drug discovery: Plasmodium proteasomes in the fight against malaria

Abstract

The proteasome is a protease complex essential in all eukaryotes and a well-established target for cancer therapy. Our initial cryo-EM structure of the human 20S proteasome, bound to a substrate analogue inhibitor molecule, served as proof of principle that cryo-EM is a realistic tool for structure-based drug design, with its own advantages compared with other methods of structure determination. Within this context, we extended our cryo-EM studies to validate the Plasmodium falciparum proteasome as an antimalarial target. According to the World Health Organization, in 2020 Plasmodium falciparum malaria is estimated to have caused 627,000 deaths worldwide, the majority of which were young children in sub-Saharan Africa. The recent rise and spreading of parasites resistant to existing therapies, including to the frontline artemisinin derivatives, urges the development of new treatments. It has been known that inhibition of the Plasmodium proteasome is lethal, but high-resolution structural information is needed to identify differences in their active sites, compared with the human complex, that can be used to drive drug specificity. While X-ray crystallography has been widely used in the development of proteasome inhibitors, the Plasmodium proteasome evades crystallisation as it is difficult to prepare in sufficient amounts from cultured parasites. We therefore determined cryo-EM structures of the Plasmodium falciparum proteasome bond to new specific inhibitors. Our initial structure, at a resolution of 3.6 Å, revealed the molecular basis for ligand specificity towards the parasite proteasome active sites and provided a framework to guide in the improvement of the prototype ligand into a potent new antimalarial. Our most recent data, with a second-generation specific inhibitor and at considerably higher resolution (2.8 Å), provided further information to guide drug development, while also revealing unexpected advantages of using cryo-EM in the development of Plasmodium proteasome targeting antimalarials.