Conformational landscapes for KMSKS loop in tyrosyl-tRNA synthetases.

Protein synthesis requires accurate charging of tRNA with cognate amino acid as catalyzed by aminoacyl-tRNA synthetases. Crystal structures of tyrosyl-tRNA synthetase (YRSs) show remarkably diverse conformations for the KMSKS loop, hitherto classified as "open" and "closed". This traditional classification implied that the KMSKS loop adopts different conformations depending on occupancy of active site pocket. Our structural analyses of evolutionarily derived ensemble of differentially ligated YRSs using quantitative structural criterion demonstrate intrinsic conformational heterogeneity in KMSKS loop that is independent of occupancy of active site. Differential centroid distance analyses between KMSKS motif and Rossmann fold domain reveal an intriguing bimodal distribution. These insights have been used for a more consistent re-classification of YRS conformations as either compact or extended. Our data not only reflect inherent dynamics within the conformational landscape of KMSKS loops, but also have implications for structure-based drug design efforts.