1h69: Difference between revisions

==Overview==

BACKGROUND: NAD(P)H:quinone acceptor oxidoreductase (QR1) protects animal, cells from the deleterious and carcinogenic effects of quinones and other, electrophiles. Remarkably, the same enzyme activates cancer prodrugs that, become cytotoxic only after two-electron reduction. QR1's ability to, bioactivate quinones and its elevated expression in many human solid, tumors makes this protein an excellent target for enzyme-directed drug, development. Until now, structural analysis of the mode of binding of, chemotherapeutic compounds to QR1 was based on model building using the, structures of complexes with simple substrates; no structure of complexes, of QR1 with chemotherapeutic prodrugs had been reported. RESULTS: Here we, report the high-resolution crystal structures of complexes of QR1 with, three chemotherapeutic prodrugs: RH1, a water-soluble homolog of, dimethylaziridinylbenzoquinone; EO9, an aziridinylindolequinone; and, ARH019, another aziridinylindolequinone. The structures, determined to, resolutions of 2.0 A, 2.5 A, and 1.86 A, respectively, were refined to R, values below 21% with excellent geometry. CONCLUSIONS: The structures show, that compounds can bind to QR1 in more than one orientation. Surprisingly, the two aziridinylindolequinones bind to the enzyme in different, orientations. The results presented here reveal two new factors that must, be taken into account in the design of prodrugs targeted for activation by, QR1: the enzyme binding site is highly plastic and changes to accommodate, binding of different substrates, and homologous drugs with different, substituents may bind to QR1 in different orientations. These structural, insights provide important clues for the optimization of chemotherapeutic, compounds that utilize this reductive bioactivation pathway.

==About this Structure==

[[Category: rossman fold]]