Fig. 5. Cavity 1 in turnover-2 state accommodates substrates but not inhibitors.

Vertically sliced views through E₁S-bound (left) and topotecan-bound (right) turnover-2 structures. The top row of panels shows the TMDs both as ribbons and in surface representation. The bottom row shows close-up views of cavity 1, with ABCG2 in surface representation. Bound E₁S and topotecan are shown in mixed stick/sphere representation as built in the structures. Inhibitor structures were extracted from inward-open ABCG2 structures containing these inhibitors (PDB 6ETI and 6FEQ, respectively). To place inhibitors into cavity 1 of the turnover-2 state, we aligned the phenyl moieties of the two F439 residues in PDB 6ETI or in 6FEQ with those of our turnover structures. In this way the translocation pathway of PDB 6ETI, 6FEQ, and turnover-2 are well-aligned and inhibitors can be fit. The inhibitors placed into cavity 1 of the topotecan turnover-2 emphasize the resulting steric clashes.