Structural analysis of malaria‐parasite lysyl‐tRNA synthetase provides a platform for drug development. (1st May 2013)

• Record Type: Journal Article
• Authors: Khan, Sameena; Garg, Ankur; Camacho, Noelia; Van Rooyen, Jason; Kumar Pole, Anil; Belrhali, Hassan; Ribas de Pouplana, Lluis; Sharma, Vinay; Sharma, Amit
• Is Part Of: Acta crystallographica. Volume 69:Part 5(2013:May)
• Page Start: 785
• Page End: 795
• Publication Date: 2013-05-01
• Subjects: malaria -- aminoacyl‐tRNA synthetases -- cladosporin; Biomolecules -- Structure -- Periodicals; Physical biochemistry -- Periodicals; X-ray crystallography -- Periodicals; Crystallography -- Periodicals; 572
• DOI: 10.1107/S0907444913001923
• Languages: English
• ISSNs: 0907-4449

Abstract

Abstract : Aminoacyl‐tRNA synthetases are essential enzymes that transmit information from the genetic code to proteins in cells and are targets for antipathogen drug development. Elucidation of the crystal structure of cytoplasmic lysyl‐tRNA synthetase from the malaria parasite Plasmodium falciparum ( Pf LysRS) has allowed direct comparison with human LysRS. The authors' data suggest that Pf LysRS is dimeric in solution, whereas the human counterpart can also adopt tetrameric forms. It is shown for the first time that Pf LysRS is capable of synthesizing the signalling molecule Ap4a (diadenosine tetraphosphate) using ATP as a substrate. The Pf LysRS crystal structure is in the apo form, such that binding to ATP will require rotameric changes in four conserved residues. Differences in the active‐site regions of parasite and human LysRSs suggest the possibility of exploiting Pf LysRS for selective inhibition. These investigations on Pf LysRS further validate malarial LysRSs as attractive antimalarial targets and provide new structural space for the development of inhibitors that target pathogen LysRSs selectively.