title: Structural and functional analysis of the anti-malarial drug target prolyl-tRNA synthetase.
abstract: Aminoacyl-tRNA synthetases (aaRSs) drive protein translation in cells and hence these are essential enzymes across life. Inhibition of these enzymes can halt growth of an organism by stalling protein translation. Therefore, small molecule targeting of aaRS active sites is an attractive avenue from the perspective of developing anti-infectives. Febrifugine and its derivatives like halofuginone (HF) are known to inhibit prolyl-tRNA synthetase of malaria parasite Plasmodium falciparum. Here, we present functional and crystallographic data on P. falciparum prolyl-tRNA synthetase (PfPRS). Using immunofluorescence data, we show that PfPRS is exclusively resident in the parasite cytoplasm within asexual blood stage parasites. The inhibitor HF interacts strongly with PfPRS in a non-competitive binding mode in presence or absence of ATP analog. Intriguingly, the two monomers that constitute dimeric PfPRS display significantly different conformations in their active site regions. The structural analyses presented here provide a framework for development of febrifugine derivatives that can seed development of new anti-malarials.
authors.affiliation: Structural and Computational Biology Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, 110067, India.
authors.forename: Vitul
authors.initials: V
authors.lastname: Jain
authors.forename: Haruhisa
authors.initials: H
authors.lastname: Kikuchi
authors.forename: Yoshiteru
authors.initials: Y
authors.lastname: Oshima
authors.forename: Amit
authors.initials: A
authors.lastname: Sharma
authors.forename: Manickam
authors.initials: M
authors.lastname: Yogavel
mesh_terms: D000604:Amino Acyl-tRNA Synthetases / Q000037:antagonists & inhibitors / Q000737:chemistry; D000962:Antimalarials / Q000737:chemistry*; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry*; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000201:enzymology; D010880:Piperidines / Q000737:chemistry*; D010963:Plasmodium falciparum / Q000201:enzymology*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D011799:Quinazolines / Q000737:chemistry*
chemical_list: D000962:Antimalarials; D004791:Enzyme Inhibitors; D010880:Piperidines; D015800:Protozoan Proteins; D011799:Quinazolines; C001207:febrifugine; D000604:Amino Acyl-tRNA Synthetases; C100134:prolyl T RNA synthetase