4qwt
Anaerobic crystal structure of delta413-417:GS LOX in complex with arachidonateAnaerobic crystal structure of delta413-417:GS LOX in complex with arachidonate
Structural highlights
FunctionAOSL_PLEHO Bifunctional enzyme which is responsible for allene oxide biosynthesis via a two-step reaction which involves conversion of arachidonic acid to a 8R-hydroperoxide intermediate followed by conversion of the hydroperoxide to allene oxide.[1] [2] Publication Abstract from PubMedLipoxygenases (LOX) play critical roles in mammalian biology in the generation of potent lipid mediators of the inflammatory response; consequently they are targets for the development of isoform-specific inhibitors. The regio- and stereo-specificity of the oxygenation of polyunsaturated fatty acids by the enzymes is understood in terms of the chemistry, but structural observation of the enzyme-substrate interactions is lacking. Although several LOX crystal structures are available, heretofore the rapid oxygenation of bound substrate has precluded capture of the enzyme-substrate complex, leaving a gap between chemical and structural insights. In this report we describe the 2.0 A resolution structure of 8R-LOX in complex with arachidonic acid (AA) obtained under anaerobic conditions. Subtle rearrangements, primarily in the side chains of three amino acids, allow binding of AA in a catalytically competent conformation. Accompanying experimental work supports a model in which both substrate tethering and cavity depth contribute to positioning the appropriate carbon at the catalytic machinery. Crystal Structure of a Lipoxygenase in Complex with Substrate: the Arachidonic Acid Binding Site of 8R-Lipoxygenase.,Neau DB, Bender G, Boeglin WE, Bartlett SG, Brash AR, Newcomer ME J Biol Chem. 2014 Sep 17. pii: jbc.M114.599662. PMID:25231982[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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