Plasmodium subtilisin-like protease 1 (SUB1): Insights into the active-site structure, specificity and function of a pan-malaria drug target

► Molecular modelling of subtilisin-like protease 1 (SUB1) of three human malaria pathogens shows similarity in active site. ► Experimental examination of Plasmodium falciparum (Pf)SUB1 demonstrates unusual features of the active site. ► Recombinant expression of active Plasmodium vivax (Pv)SUB1, Plasmodium knowlesi (Pk)SUB1 and Plasmodium berghei (Pb)SUB1. ► Evidence for co-evolution of SUB1 orthologues and substrates following speciation. ► Production of substrate-based inhibitors with broad activity against SUB1 from three major human malarial pathogens.