Dynamics of different arachidonic acid orientations bound to prostaglandin endoperoxide synthases.

Prostaglandin endoperoxide synthases (PGHSs) catalyze the conversion of arachidonic acid (AA) into prostaglandin endoperoxide H2. This reaction requires a specific orientation of AA within the active site, but an alternative crystallographic binding orientation for AA also exists. Since the origin of this alternative complex, and its potential relevance, have been neglected so far, we have characterized the dynamics of both orientations of AA, bound to PGHS-1 and -2, in order to obtain new insights for designing PGHSs inhibitors. Our results indicate that AA in the alternative orientation seems to be less stable, moving toward Arg120. Such potentially minor orientation of AA can be related to crystallographic complexes of anti-inflammatory agents, pointing to an alternate SAR on PGHSs inhibitors.