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Crystal Structure of Prolyl-tRNA Synthetase (PRS) from Plasmodium falciparumCrystal Structure of Prolyl-tRNA Synthetase (PRS) from Plasmodium falciparum
Structural highlights
FunctionSYP_PLAF7 Catalyzes the attachment of proline to tRNA(Pro) in a two-step reaction: proline is first activated by ATP to form Pro-AMP and then transferred to the acceptor end of tRNA(Pro) (By similarity). Functions in trans to edit the amino acid moiety from incorrectly charged Ala-tRNA(Pro). Has no activity on correctly charged Pro-tRNA(Pro) or Ala-tRNA(Ala).[1] Publication Abstract from PubMedAminoacyl-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. Structural and functional analysis of the anti-malarial drug target prolyl-tRNA synthetase.,Jain V, Kikuchi H, Oshima Y, Sharma A, Yogavel M J Struct Funct Genomics. 2014 Jul 22. PMID:25047712[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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