Intermediate trapping and laue X-ray diffraction: potential for enzyme mechanism, dynamics, and inhibitor screening.

Among the many macromolecules of biomedical interest, enzyme catalysts remain important targets for the development of inhibitors and drugs, due to our ability to directly measure inhibition constants in vitro. Crystallographic structures of enzymes allow drug screening to be carried out by computational analysis of small molecules for structural and chemical complementarity to the active site. Such methods generally rely on static target structures. The development of time-resolved crystallographic methods, including trapping of reaction intermediates and Laue diffraction, allow the comparative study of enzyme conformations at different intermediate states in the catalytic cycle, providing an experimental avenue for visualizing and exploiting discrete structural states. Such methods have clear implications for mechanistic studies and possibly for computational drug design.