Figure 4.

Superposition of 3A4 (gray) with two molecules of ketoconazole (KLN) bound in the active site (PDB code 2V0M) with apo 3A5 (yellow) using ALIGN with defaults in PyMOL. Portions of the proteins are shown as cartoons displaying secondary and tertiary structure. The imidazole nitrogen of the lower ketoconazole molecule is ligated to the heme iron, and together with the neighboring dichlorophenyl group, they displace a portion of helix I outward. A second molecule of ketoconazole stacks above the first in anti-parallel orientation with dichlorophenyl moiety residing in the entrance channel. The conformation of the helix F–G regions of the two structures are overlapped to greater extent than seen for structures of the 3A5 and 3A4 ritonavir complexes, and the 3A4 active site is greatly enlarged by the presence of the two ketoconazole molecules.