Structural basis for ATP regulation of human 5-lipoxygenase

Abstract

5-Lipoxygenase catalyzes the committed step in the biosynthesis of the powerful proinflammatory leukotrienes and pro-resolving anti-inflammatory lipoxins. Here we present a 3.3 [A] cryo-EM structure of wild type 5-lipoxygenase in complex with ATP, one of its most important allosteric regulators. The nucleotide is located in a positively charged pocket of the catalytic domain and held in place by a complex network of amino acid side chains and backbone carbonyl and amino groups. Mutagenetic analysis suggests that ATP binding and action is primarily mediated via Lys320, assisted by Gln657. Further atomistic simulations demonstrate that ATP binding induces movements of the PLAT domain coupled to conformational rearrangements at the active center. These findings provide important structural and regulatory insights to a key enzyme in leukotriene biosynthesis, thus aiding in design of new antiphlogistic drugs.