Designing novel anti-malarial drugs
Researchers using the NE-CAT 24-ID-C beamline at the APS report the first crystal structure of a eukaryotic homolog of bacterial ClpS from the malaria apicomplexan parasite Plasmodium falciparum (Pfal). This research opens new venues for the design of novel anti-malarial drugs aimed at disrupting parasite-specific protein quality control pathways.
The apicomplexan parasite Plasmodium falciparum is the causative agent of malaria, which accounts for almost 1 million fatalities worldwide every year and about 500 million infections, mostly in Sub-Saharan Africa, Asia, and South America. The spread of drug resistance constitutes a serious threat to the effective control or eradication of the disease.
The N-end rule pathway uses an evolutionarily conserved mechanism in bacteria and eukaryotes that marks proteins for degradation by ATP-dependent chaperones and proteases such as the Clp chaperones and proteases. Specific N-terminal amino acids (N-degrons) are sufficient to target substrates for degradation. In bacteria, the ClpS adaptor binds and delivers N-end rule substrates for their degradation upon association with the ClpA/P chaperone/protease. Here, we report the first crystal structure, solved at 2.7 Å resolution, of a eukaryotic homolog of bacterial ClpS from the malaria apicomplexan parasite Plasmodium falciparum (Pfal). Despite limited sequence identity, Plasmodium ClpS is very similar to bacterial ClpS. Akin to its bacterial orthologs, plasmodial ClpS harbors a preformed hydrophobic pocket whose geometry and chemical properties are compatible with the binding of N-degrons.
However, while the N-degron binding pocket in bacterial ClpS structures is open and accessible, the corresponding pocket in Plasmodium ClpS is occluded by a conserved surface loop that acts as a latch. Despite the closed conformation observed in the crystal, we show that, in solution, Pfal-ClpS binds and discriminates peptides mimicking bona fide N-end rule substrates. The presence of an apicoplast targeting peptide suggests that Pfal-ClpS localizes to this plastid-like organelle characteristic of all Apicomplexa and hosting most of its Clp machinery. By analogy with the related ClpS1 from plant chloroplasts and cyanobacteria, Plasmodium ClpS likely functions in association with ClpC in the apicoplast. Our findings open new venues for the design of novel anti-malarial drugs aimed at disrupting parasite-specific protein quality control pathways.
Andrew P. AhYoung, Antoine Koehl, Christina L. Vizcarra, Duilio Cascio and Pascal F. Egea, “Structure of a Putative ClpS N-end Rule Adaptor Protein from the Malaria Pathogen Plasmodium falciparum,” Protein Science, Article, DOI: 10.1002/pro.2868, Published Online January 13, 2016.