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A potent and selective PARP11 inhibitor suggests coupling between cellular localization and catalytic activity

DOI: 10.1016/j.chembiol.2018.09.011 DOI Help

Authors: Ilsa T. Kirby (Oregon Health & Science University) , Ana Kojic (European Molecular Biology Laboratory (EMBL)) , Moriah R. Arnold (Oregon Health & Science University) , Ann-Gerd Thorsell (Karolinska Institutet) , Tobias Karlberg (Karolinska Institutet) , Anke Vermehren-Schmaedick (Oregon Health & Science University) , Raashi Sreenivasan (Oregon Health & Science University) , Carsten Schultz (Oregon Health & Science University; European Molecular Biology Laboratory (EMBL)) , Herwig Schüler (Karolinska Institutet) , Michael S. Cohen (Oregon Health & Science University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Cell Chemical Biology

State: Published (Approved)
Published: October 2018

Abstract: Poly-ADP-ribose polymerases (PARPs1-16) play pivotal roles in diverse cellular processes. PARPs that catalyze poly-ADP-ribosylation (PARylation) are the best characterized PARP family members because of the availability of potent and selective inhibitors for these PARPs. There has been comparatively little success in developing selective small-molecule inhibitors of PARPs that catalyze mono-ADP-ribosylation (MARylation), limiting our understanding of the cellular role of MARylation. Here we describe the structure-guided design of inhibitors of PARPs that catalyze MARylation. The most selective analog, ITK7, potently inhibits the MARylation activity of PARP11, a nuclear envelope-localized PARP. ITK7 is greater than 200-fold selective over other PARP family members. Using live-cell imaging, we show that ITK7 causes PARP11 to dissociate from the nuclear envelope. These results suggest that the cellular localization of PARP11 is regulated by its catalytic activity.

Journal Keywords: PARPs; ADP-ribosylation; MARylation; PARP11; nuclear envelope

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength) , I24-Microfocus Macromolecular Crystallography

Added On: 24/10/2018 09:49

Discipline Tags:

Life Sciences & Biotech Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)