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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
- 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.
- Subjects :
- Lysine-tRNA Ligase
Models, Molecular
Protein Conformation
Molecular Sequence Data
Plasmodium falciparum
Biology
Crystallography, X-Ray
chemistry.chemical_compound
Adenosine Triphosphate
Structural Biology
Catalytic Domain
Humans
Amino Acid Sequence
Conserved Sequence
chemistry.chemical_classification
DNA ligase
Binding Sites
Aminoacyl tRNA synthetase
General Medicine
Genetic code
biology.organism_classification
Malaria
Molecular Docking Simulation
Enzyme
chemistry
Drug development
Biochemistry
Cytoplasm
Drug Design
Ap4A
Dinucleoside Phosphates
Subjects
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