Cryo-EM structures of human arachidonate 12S-lipoxygenase bound to endogenous and exogenous inhibitors

JI Mobbs; KA Black; M Tran; WAC Burger; H Venugopal; TR Holman; M Holinstat; DM Thal; A Glukhova

Journal article

Cryo-EM structures of human arachidonate 12S-lipoxygenase bound to endogenous and exogenous inhibitors

JI Mobbs, KA Black, M Tran, WAC Burger, H Venugopal, TR Holman, M Holinstat, DM Thal, A Glukhova

Blood | Published : 2023

DOI: 10.1182/blood.2023020441

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Abstract

Human 12-lipoxygenase (12-LOX) is a key enzyme involved in platelet activation, and the regulation of its activity has been targeted for the treatment of heparin-induced thrombocytopenia. Despite the clinical importance of 12-LOX, the exact mechanisms by which it affects platelet activation are not fully understood, and the lack of structural information has limited drug discovery efforts. In this study, we used single-particle cryo-electron microscopy to determine high-resolution structures (1.7-2.8 Å) of human 12-LOX. Our results showed that 12-LOX can exist in multiple oligomeric states, from monomer to hexamer, which may affect its catalytic activity and membrane association. We also ide..

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University of Melbourne Researchers

Alisa Glukhova Author

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Awarded by National Institutes of Health

Funding Acknowledgements

The authors acknowledge the use of facilities within the Monash Ramaciotti Cryo-EM platform and the Ian Holmes Imaging Centre at the Bio21 Molecular Science and Biotechnology Institute. The computational work was supported by the MASSIVE high-performance data processing facility (MASSIVE HPC) (https:// www.massive.org.au). This work was supported by funding from the Walter and Eliza Hall Institute of Medical Research (WEHI), The University of Melbourne, and the estate of Akos and Marjorie Talon. A.G. is a CSL, Australia CentenaryFellow. D.M.T. is supported by a National Health and Medical Research Council of Australia Early Career Investigator grant (1138448). M.H. is supported by National Institutes of Health, National Institute of General Medical Sciences grant R35 GM131835.r Fellow. D.M.T. is supported by a National Health and Medical Research Council of Australia Early Career Investigator grant (1138448) . M.H. is supported by National Institutes of Health, National Institute of General Medical Sciences grant R35 GM131835.