A detailed study of the crystal structure of Poly(ADP-ribose) polymerase-1 (PARP-1) complexed with a double-stranded DNA break has identified specific domains on the enzyme that could represent targets for the design of more specific PARP-1 inhibitors. PARP-1 is a protein that detects and responds to DNA breaks, and inhibitors targeting the enzyme are being tested in anticancer trials.
PARP-1 inhibitors candidates, however, target the enzyme’s catalytic active site, which is similar to the catalytic sites of other PARP-like proteins that carry out essential cellular functions. This increases the likelihood that PARP-1 inhibition will have adverse off-target effects.
Researchers at Thomas Jefferson University’s the Kimmel Cancer Center have now found that it may be possible to inhibit PARP-1 without having to target its active site directly. Their x-ray crystallographic studies have shown that the Zn1, Zn3, and WGR domains on the PARP enzyme all need to come together to link the DNA damage interface with the catalytic domain of the enzyme in order to catalyze DNA repair.
The hope is that designing molecules that prevent these sites from coming together will block PARP-1 catalytic activity and provide more specific PARP-1 enzyme inhibition than active site inhibitors, states lead researcher John M. Pascal, Ph.D. “Rather than screen for inhibitors with catalytic activity as a readout, we can screen for inhibitors that disrupt the communication between the PARP-1 domains, which would in turn shut down catalytic activity.”
Dr. Pascal and colleagues report their findings in Science in a paper titled “Structural Basis for DNA Damage-Dependent Poly(ADP-ribosyl)ation by Human PARP-1.”