Human 12-lipoxygenase (12-LOX) is a key enzyme involved in platelet activation and regulation of its activity has been targeted for treatment of heparin-induced thrombocytopenia. Despite the clinical importance of 12-LOX, the exact mechanisms of how 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 the high-resolution structures (1.7 Å …