Structural and functional insights into peptidyl-tRNA hydrolase

•Peptidyl-tRNA hydrolase (Pth) acts as a rescue factor of the stalled ribosomes.•The two classes of Pth, Pth and Pth2 vary in sequence and structural features.•The basic three dimensional structure of Pth from bacterial species is conserved.•Substrate binding sites of Pth from various species show critical differences.•Study on complexes of Pth can throw light for the design of novel antibiotics.

Peptidyl-tRNA hydrolase is an essential enzyme which acts as one of the rescue factors of the stalled ribosomes. It is an esterase that hydrolyzes the ester bond in the peptidyl-tRNA molecules, which are products of ribosome stalling. This enzyme is required for rapid clearing of the peptidyl-tRNAs, the accumulation of which in the cell leads to cell death. Over the recent years, it has been heralded as an attractive drug target for antimicrobial therapeutics. Two distinct classes of peptidyl-tRNA hydrolase, Pth and Pth2, have been identified in nature. This review gives an overview of the structural and functional aspects of Pth, along with its sequence and structural comparison among various species of bacteria. While the mode of binding of the substrate to Pth and the mechanism of hydrolysis are still speculated upon, the structure-based drug design using this protein as the target is still largely unexplored. This review focuses on the structural features of Pth, giving a direction to structure-based drug design on this protein.