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Two Conformations of Mammalian Cytochrome P450 2B4 Covalently Bound to the Mechanism‐Based Inactivator tert‐Butylphenylacetylene

Two x‐ray crystal structures of rabbit cytochrome P450 2B4 bound to the mechanism‐based inactivator tert‐butylphenylacetylene (tBPA) have been determined. Both structures show an oxygenated metabolite of tBPA covalently linked to Thr302 of helix I, which places the molecule above the plane of the heme. These results are consistent with a previous study that identified Thr302 as the site modified during inactivation. In each structure, the core of 2B4 remains unchanged, but the arrangement of plastic regions differs. This results in one structure that is compact and closed, which shares high similarity with previously determined 2B4 structures bound to 4‐CPI, 1‐CPI, ticlopidine, or clopidogrel, and with the human 2B6–4‐CPI complex. In this conformation, tBPA points toward helix B′, making a 40° angle with helix I, which is in agreement with previously performed in silico experiments. However, dimerization of 2B4 in the other structure, which is caused by movement of the B/C loop and helices F through G, alters the position of tBPA. This structure is more similar to the open conformations of 2B4 in the presence of 1‐PBI or bifonazole, which also dimerize. In this case, tBPA lies almost parallel to the plane of the heme due to the presence of helix F′ of the opposite monomer entering the active site to stabilize the dimer. These results could explain how tBPA‐modified 2B4 is still able to oxidize some substrates, but not others.