6WE2

Human PARP14 (ARTD8), catalytic fragment in complex with RBN012759

Summary for 6WE2

• Entry DOI: 10.2210/pdb6we2/pdb
• Descriptor: Isoform 1 of Protein mono-ADP-ribosyltransferase PARP14, 7-(cyclopropylmethoxy)-5-fluoro-2-{[(trans-4-hydroxycyclohexyl)sulfanyl]methyl}quinazolin-4(3H)-one, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: parp14, artd8, monoparp, adp ribosylation, inhibitor complex, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 44127.06

Authors

Swinger, K.K.,Schenkel, L.B.,Kuntz, K.W. (deposition date: 2020-04-01, release date: 2021-03-24, Last modification date: 2024-10-30)

Primary citation

Schenkel, L.B.,Molina, J.R.,Swinger, K.K.,Abo, R.,Blackwell, D.J.,Lu, A.Z.,Cheung, A.E.,Church, W.D.,Kunii, K.,Kuplast-Barr, K.G.,Majer, C.R.,Minissale, E.,Mo, J.R.,Niepel, M.,Reik, C.,Ren, Y.,Vasbinder, M.M.,Wigle, T.J.,Richon, V.M.,Keilhack, H.,Kuntz, K.W.
A potent and selective PARP14 inhibitor decreases protumor macrophage gene expression and elicits inflammatory responses in tumor explants.
Cell Chem Biol, 28:1158-, 2021

PubMed Abstract: PARP14 has been implicated by genetic knockout studies to promote protumor macrophage polarization and suppress the antitumor inflammatory response due to its role in modulating interleukin-4 (IL-4) and interferon-γ signaling pathways. Here, we describe structure-based design efforts leading to the discovery of a potent and highly selective PARP14 chemical probe. RBN012759 inhibits PARP14 with a biochemical half-maximal inhibitory concentration of 0.003 μM, exhibits >300-fold selectivity over all PARP family members, and its profile enables further study of PARP14 biology and disease association both in vitro and in vivo. Inhibition of PARP14 with RBN012759 reverses IL-4-driven protumor gene expression in macrophages and induces an inflammatory mRNA signature similar to that induced by immune checkpoint inhibitor therapy in primary human tumor explants. These data support an immune suppressive role of PARP14 in tumors and suggest potential utility of PARP14 inhibitors in the treatment of cancer.

PubMed: 33705687
DOI: 10.1016/j.chembiol.2021.02.010

Experimental method

X-RAY DIFFRACTION (2.66 Å)