7L9Y

Human PARP14 (ARTD8), catalytic fragment in complex with RBN012042

Summary for 7L9Y

• Entry DOI: 10.2210/pdb7l9y/pdb
• Descriptor: Protein mono-ADP-ribosyltransferase PARP14, 7-(cyclopentylamino)-5-fluoro-2-{[(piperidin-4-yl)sulfanyl]methyl}quinazolin-4(3H)-one, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: parp14, artd8, monoparp, adp ribosylation, inhibitor complex, transferase-inhibitor complex, transferase, transferase/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 90621.80

Authors

Dorsey, B.W.,Swinger, K.K.,Schenkel, L.B.,Church, W.D.,Perl, N.R.,Vasbinder, M.M.,Wigle, T.J.,Kuntz, K.W. (deposition date: 2021-01-05, release date: 2021-04-21, Last modification date: 2023-10-18)

Primary citation

Wigle, T.J.,Ren, Y.,Molina, J.R.,Blackwell, D.J.,Schenkel, L.B.,Swinger, K.K.,Kuplast-Barr, K.,Majer, C.R.,Church, W.D.,Lu, A.Z.,Mo, J.,Abo, R.,Cheung, A.,Dorsey, B.W.,Niepel, M.,Perl, N.R.,Vasbinder, M.M.,Keilhack, H.,Kuntz, K.W.
Targeted Degradation of PARP14 Using a Heterobifunctional Small Molecule.
Chembiochem, 22:2107-2110, 2021

PubMed Abstract: PARP14 is an interferon-stimulated gene that is overexpressed in multiple tumor types, influencing pro-tumor macrophage polarization as well as suppressing the antitumor inflammation response by modulating IFN-γ and IL-4 signaling. PARP14 is a 203 kDa protein that possesses a catalytic domain responsible for the transfer of mono-ADP-ribose to its substrates. PARP14 also contains three macrodomains and a WWE domain which are binding modules for mono-ADP-ribose and poly-ADP-ribose, respectively, in addition to two RNA recognition motifs. Catalytic inhibitors of PARP14 have been shown to reverse IL-4 driven pro-tumor gene expression in macrophages, however it is not clear what roles the non-enzymatic biomolecular recognition motifs play in PARP14-driven immunology and inflammation. To further understand this, we have discovered a heterobifunctional small molecule designed based on a catalytic inhibitor of PARP14 that binds in the enzyme's NAD -binding site and recruits cereblon to ubiquitinate it and selectively target it for degradation.

PubMed: 33838082
DOI: 10.1002/cbic.202100047

Experimental method

X-RAY DIFFRACTION (2.25 Å)