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The 2-oxoglutarate (2OG)-dependent non-heme enzyme FtmOx1 catalyzes the endoperoxide biosynthesis of verruculogen. Although several mechanistic studies have been carried out, the catalytic mechanism of FtmOx1 is not well determined owingtothe lackofareliable complex structure of FtmOx1 with fumitremorgin B. Herein we providet he X-ray crystal structure of the ternary complex FtmOx1•2OG•fumitremorgin Bataresolution of 1.22 .Our structures showthat the binding of fumitremorgin Bi nduces significant compression of the active pocket and that Y68 is in close proximityt o C26 of the substrate.F urther MD simulation and QM/MM calculations support aCarC-like mechanism, in which Y68 acts as the Hatom donor for quenching the C26-centered substrate radical. Our results are consistent with all available experimental data and highlight the importance of accurate complex structures in the mechanistic study of enzymatic catalysis.