Figure 5.

Tentative model for binding of steroids, ATP, MANT-ATP, and flavonoids to adjacent nucleotide- and modulator-binding sites within the cytosolic H₆-NBD2 domain of P-glycoprotein. Previous work with purified cytosolic NBD1 domain (10) showed the existence of a steroid-binding region (hexagon) adjacent to the nucleotide site (rectangle), where RU 486 and ATP bind separately or together, and a mutually exclusive MANT-ATP binding, indicating partial overlapping of the vicinal steroid-binding region by the hydrophobic MANT group. These results indicate a similar behavior of cytosolic NBD2 (A–C), and additionally show that flavonoids are bifunctional modulators that partly overlap both ATP and steroid adjacent sites (D).