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In all living cells, aminoacyl-tRNA synthetases (AARSs) conduct the first step in protein translation - the attachment of a specific amino acid to tRNAs bearing the anticodons cognate for that amino acid. Thus, 20 synthetases, cognate for the 20 amino acids, establish the genetic code. Modern AARSs are highly evolved enzymes which adhere to complex recognition and editing mechanisms to achieve specificity for their cognate substrates and avoid errors in protein translation. Such errors are detrimental to cell health and naturally occurring mutations in synthetases have been linked to certain neuropathies in humans and mice. In addition to their aminoacylation function, some synthetases are key players in other important cellular functions such as cytokine response in mammalian cells shown to mediate angiogenic and angiostatic processes. Using
X-ray crystallography as a tool, we study the structural basis of
AARSs amino acid specificities, elucidate their tRNA recognition
modes and shed light on enzymatic mechanism. Further, 3-dimensional
structures allow for the elucidation of mechanisms of the novel
cytokine functions associated with aminoacyl-tRNA synthetases. Such
understanding provides the foundation for design of biologics as
inhibitors of disease-causing angiogenesis in humans. |
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