Enhanced amino acid selection in fully evolved tryptophanyl-trna synthetase, relative to its urzyme, requires domain motion sensed by the D1 switch, a remote dynamic packing motif

Abstract

Background: Amino acid selection by tryptophanyl-tRNA synthetase (TrpRS) requires intermodular coupling. Results: Dynamic repacking of four side chains increases amino acid specificity 500-fold in contemporary TrpRS by reducing pocket size near the transition state. Conclusion: An ancient tertiary packing motif not only activates the catalytic Mg2 ion during catalysis, but also determines cognate amino acid specificity. Significance: Allosteric enforcement of specificity increases robustness to mutation. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc..