Structural and evolutionary insights into understudied bacterial serine-threonine pseudokinase families

Pseudokinases, once considered catalytically inactive remnants of evolution, have emerged as key regulators of numerous fundamental biological processes. While eukaryotic pseudokinases have attracted significant attention, bacterial pseudokinases remain largely unexplored experimentally. Recent advances in sequence analysis and structural modeling have identified and characterized multiple conserved bacterial pseudokinase families, each with distinct predicted catalytic impairments but unknown functions. This review delves into their classification, structural features, and evolutionary adaptation. We also highlight the significance of bacterial pseudokinases in host-microbe interactions and their emerging potential as therapeutic targets. By integrating bioinformatics with experimental approaches, future research is poised to uncover the biological functions of bacterial pseudokinases, providing new insights into microbial signaling mechanisms and revealing new strategies to interrogate bacterial cell signaling, including pseudokinase drivers of infection and antimicrobial drug resistance.