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Structural analysis of malaria-parasite lysyl-tRNA synthetase provides a platform for drug development

Structural analysis of malaria-parasite lysyl-tRNA synthetase provides a platform for drug development

Authors :
Vinay Sharma
Anil Kumar Pole
Lluís Ribas de Pouplana
Noelia Camacho
Hassan Belrhali
Sameena Khan
Jason Van Rooyen
Amit Sharma
Ankur Garg
Source :
Acta Crystallographica Section D Biological Crystallography. 69:785-795
Publication Year :
2013
Publisher :
International Union of Crystallography (IUCr), 2013.

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 (PfLysRS) has allowed direct comparison with human LysRS. The authors' data suggest that PfLysRS is dimeric in solution, whereas the human counterpart can also adopt tetrameric forms. It is shown for the first time that PfLysRS is capable of synthesizing the signalling molecule Ap4a (diadenosine tetraphosphate) using ATP as a substrate. The PfLysRS 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 PfLysRS for selective inhibition. These investigations on PfLysRS further validate malarial LysRSs as attractive antimalarial targets and provide new structural space for the development of inhibitors that target pathogen LysRSs selectively.

Details

ISSN :
09074449
Volume :
69
Database :
OpenAIRE
Journal :
Acta Crystallographica Section D Biological Crystallography
Accession number :
edsair.doi.dedup.....4ff11140d9c7145c997c258ad976f040
Full Text :
https://doi.org/10.1107/s0907444913001923