6W65

Human PARP16 in complex with RBN010860

Summary for 6W65

• Entry DOI: 10.2210/pdb6w65/pdb
• Related: 4F0D 6HXR 6HXS
• Descriptor: Protein mono-ADP-ribosyltransferase PARP16, 5-{5-[(piperidin-4-yl)oxy]-2H-isoindol-2-yl}-4-(trifluoromethyl)pyridazin-3(2H)-one, CITRIC ACID, ... (7 entities in total)
• Functional Keywords: adp-ribose, parp16, artd15, artd transferase domain, adp-ribosylation, transferase-transferase inhibitor complex, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 3
• Total formula weight: 96232.48

Authors

Swinger, K.K.,Wigle, T.J.,Kuntz, K.W. (deposition date: 2020-03-16, release date: 2020-10-07, Last modification date: 2024-03-06)

Primary citation

Wigle, T.J.,Blackwell, D.J.,Schenkel, L.B.,Ren, Y.,Church, W.D.,Desai, H.J.,Swinger, K.K.,Santospago, A.G.,Majer, C.R.,Lu, A.Z.,Niepel, M.,Perl, N.R.,Vasbinder, M.M.,Keilhack, H.,Kuntz, K.W.
In Vitro and Cellular Probes to Study PARP Enzyme Target Engagement.
Cell Chem Biol, 27:877-887.e14, 2020

PubMed Abstract: Poly(ADP-ribose) polymerase (PARP) enzymes use nicotinamide adenine dinucleotide (NAD) to modify up to seven different amino acids with a single mono(ADP-ribose) unit (MARylation deposited by PARP monoenzymes) or branched poly(ADP-ribose) polymers (PARylation deposited by PARP polyenzymes). To enable the development of tool compounds for PARP monoenzymes and polyenzymes, we have developed active site probes for use in in vitro and cellular biophysical assays to characterize active site-directed inhibitors that compete for NAD binding. These assays are agnostic of the protein substrate for each PARP, overcoming a general lack of knowledge around the substrates for these enzymes. The in vitro assays use less enzyme than previously described activity assays, enabling discrimination of inhibitor potencies in the single-digit nanomolar range, and the cell-based assays can differentiate compounds with sub-nanomolar potencies and measure inhibitor residence time in live cells.

PubMed: 32679093
DOI: 10.1016/j.chembiol.2020.06.009

Experimental method

X-RAY DIFFRACTION (2.13 Å)