Capturing LTA

Leukotriene B4 (LTB4) is a one of the most potent chemotactic agents known to date and participates in leukocyte recruitment during the innate immune response. Leukotriene A4 hydrolase/aminopeptidase (LTA4H) catalyzes the committed step in LTB4 biosynthesis. Here we report high-resolution crystal structures of LTA4H in complex with its highly labile substrate LTA4, which reveal the structural basis for the enzyme’s unique epoxide hydrolase mechanism. Moreover, we show that LTA4H undergoes domain movements, which gates the hydrophobic cavity for entrance of LTA4 followed by induced fit. Our results provide new insights to the mechanism of LTA4H and structure-based drug design.