How methionyl-tRNA synthetase creates its amino acid recognition pocket upon l-methionine binding

Amino acid selection by aminoacyl-tRNA synthetases requires efficient mechanisms to avoid incorrect charging of the cognate tRNAs. A proofreading mechanism prevents Escherichia coli methionyl-tRNA synthetase (EcMet-RS) from activating in vivo l-homocysteine, a natural competitor of l-methionine recognised by the enzyme. The crystal structure of the complex between EcMet-RS and l-methionine solved at 1.8 Å resolution exhibits some conspicuous differences with the recently published free enzyme structure. Thus, the methionine δ-sulphur atom replaces a water molecule H-bonded to Leu13N and Tyr260Oη in the free enzyme. Rearrangements of aromatic residues enable the protein to form a hydrophobic pocket around the ligand side-chain. The subsequent formation of an extended water molecule network contributes to relative displacements, up to 3 Å, of several domains of the protein. The structure of this complex supports a plausible mechanism for the selection of l-methionine versus l-homocysteine and suggests the possibility of information transfer between the different functional domains of the enzyme.