Conformational flexibility in mammalian 15S‐lipoxygenase: Reinterpretation of the crystallographic data

Lipoxygenases (LOXs) are a family of nonheme iron dioxygenases that catalyze the regioselective and stereospecific hydroperoxidation of polyunsaturated fatty acids, and are involved in a variety of inflammatory diseases and cancers. The crystal structure of rabbit 15S‐LOX1 that was reported by Gillmor et al. in 1997 has played key roles for understanding the properties of mammalian LOXs. In this structure, three segments, including 12 residues in the superficial α2 helix, are absent and have usually been described as “disordered.” By reinterpreting the original crystallographic data we were able to elucidate two different conformations of the molecule, both having well ordered α2 helices. Surprisingly, one molecule contained an inhibitor and the other did not, thereby adopting a closed and an open form, respectively. They differed in the conformation of the segments that were absent in the original structure, which is highlighted by a 12 Å movement of α2. Consequently, they showed a difference in the size and shape of the substrate‐binding cavity. The new model should provide new insight into the catalytic mechanism involving induced conformational change of the binding pocket. It may also be helpful for the structure‐based design of LOX inhibitors. Proteins 2008. © 2007 Wiley‐Liss, Inc.