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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 289 31905-31913 (2014)
Cited: 37 times
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Abstract

Lipoxygenases (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 Ã… resolution structure of 8R-LOX in complex with arachidonic acid obtained under anaerobic conditions. Subtle rearrangements, primarily in the side chains of three amino acids, allow binding of arachidonic acid 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.

Reviews - 4qwt mentioned but not cited (3)

  1. Newcomer ME, Brash AR. Protein Sci 24 298-309 (2015)
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Articles - 4qwt mentioned but not cited (8)

  1. Neau DB, Bender G, Boeglin WE, Bartlett SG, Brash AR, Newcomer ME. J Biol Chem 289 31905-31913 (2014)
  2. Wennman A, Oliw EH, Karkehabadi S, Chen Y. J Biol Chem 291 8130-8139 (2016)
  3. Wennman A, Magnuson A, Hamberg M, Oliw EH. J Lipid Res 56 1606-1615 (2015)
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  8. Kaur D, Dorion S, Jmii S, Cappadocia L, Bede JC, Rivoal J. J Biol Chem 299 102898 (2023)


Reviews citing this publication (5)

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Articles citing this publication (21)

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  18. Pakhomova S, Boeglin WE, Neau DB, Bartlett SG, Brash AR, Newcomer ME. Protein Sci 28 920-927 (2019)
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