Figure 2.

The F–F′ loop in the CYP3A5–CBZ crystal structure adopts a novel conformation. (a) The F–F′ loop (residues 211–218) adopts a different conformation in the CBZ-bound CYP3A5 structure (blue) than that in the ritonavir-bound (PDB: 5VEU, green) and glycerol-bound (PDB: 6MJM, yellow) CYP3A5 structures. The entire monomer was used to align the three structures. (b) The F–F′ loop (cyan) adopts a conformation that places F213 and G214 (orange) near CBZ (yellow). This conformation is potentially stabilized in solution by hydrophobic interactions between F210, F213, F215, F220, and F304. (c) The F–F′ loop conformation in the CYP3A5–CBZ complex is not present in CYP3A4 crystal structures. Alignment of the F–F′ loop (residues 211–218) of the CYP3A5-CBZ complex (cyan) with residues 211–218 of all 77 CYP3A4 crystal structures (white) published to date shows that the F–F′ loop conformation in the CYP3A5–CBZ complex is unique. Additionally, D214 of CYP3A4 is not specifically directed toward the ligand-binding pocket. The entire monomer was used to create the alignment. (d) Replacing G214 with D214 (orange) in CYP3A5 prevents the F–F′ loop from forming the conformation found in the CYP3A5–CBZ crystal structure. D214 rotamers 1 and 3 would sterically clash with F213, whereas rotamer 2 would protrude into the hydrophobic pocket. Surface shown for residues F213, G214, F215, and F220.