X-ray crystal structure and specificity of the Toxoplasma gondii ME49 TgAPN2. Issue 19 (12th October 2020)

• Record Type: Journal Article
• Authors: Marijanovic, Emilia M.; Weronika Swiderska, Karolina; Andersen, James; Aschenbrenner, Jasmin C.; Webb, Chaille T.; Drag, Marcin; Drinkwater, Nyssa; McGowan, Sheena
• Is Part Of: Biochemical journal. Volume 477:Issue 19(2020)
• Page Start: 3819
• Page End: 3832
• Publication Date: 2020-10-12
• Subjects: aminopeptidase N -- M1 aminopeptidase -- metalloproteases -- PfA-M1 -- Toxoplasma gondii; Biochemistry -- Periodicals; 572
• DOI: 10.1042/BCJ20200569
• Languages: English
• ISSNs: 0264-6021

Abstract

Abstract : Toxoplasmosis is a parasitic disease caused by infection with Toxoplasma gondii that currently has few therapeutic options. The M1 aminopeptidase enzymes have been shown to be attractive targets for anti-parasitic agents and/or vaccine candidates, suggesting potential to re-purpose inhibitors between parasite M1 aminopeptidase targets. The M1 aminopeptidase Tg APN2 has been suggested to be a potential new drug target for toxoplasmosis. Here we investigate the structure and function of Tg APN2, a homologue of the antimalarial drug target Pf A-M1, and evaluate the capacity to use inhibitors that target Pf A-M1 against Tg APN2. The results show that despite a similar overall fold, the Tg APN2 has a unique substrate specificity and inhibition profile. Sequence and structure differences are investigated and show how comparative structure-activity relationships may provide a route to obtaining potent inhibitors of Tg APN2.