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Biochemistry. 1998 Mar 17;37(11):3893-900.

Inhibitor and NAD+ binding to poly(ADP-ribose) polymerase as derived from crystal structures and homology modeling.

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Institut für Organische Chemie und Biochemie, Freiburg im Breisgau, Germany.


Inhibitors of poly(ADP-ribose) polymerase (PARP, EC are of clinical interest because they have potential for improving radiation therapy and chemotherapy of cancer. The refined binding structures of four such inhibitors are reported together with the refined structure of the unligated catalytic fragment of the enzyme. Following their design, all inhibitors bind at the position of the nicotinamide moiety of the substrate NAD+. The observed binding mode suggests inhibitor improvements that avoid other NAD(+)-binding enzymes. Because the binding pocket of NAD+ has been strongly conserved during evolution, the homology with ADP-ribosylating bacterial toxins could be used to extend the bound nicotinamide, which is marked by the inhibitors, to the full NAD+ molecule.

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