6EK3

PARP15 CATALYTIC DOMAIN MUTANT (Y598L) IN COMPLEX WITH OUL35

Summary for 6EK3

• Entry DOI: 10.2210/pdb6ek3/pdb
• Descriptor: Poly [ADP-ribose] polymerase 15, 4-(4-aminocarbonylphenoxy)benzamide (3 entities in total)
• Functional Keywords: inhibitor, oul35, signaling protein, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 51291.40

Authors

Maksimainen, M.M.,Lehtio, L. (deposition date: 2017-09-25, release date: 2018-07-25, Last modification date: 2024-01-17)

Primary citation

Murthy, S.,Desantis, J.,Verheugd, P.,Maksimainen, M.M.,Venkannagari, H.,Massari, S.,Ashok, Y.,Obaji, E.,Nkizinkinko, Y.,Luscher, B.,Tabarrini, O.,Lehtio, L.
4-(Phenoxy) and 4-(benzyloxy)benzamides as potent and selective inhibitors of mono-ADP-ribosyltransferase PARP10/ARTD10.
Eur J Med Chem, 156:93-102, 2018

PubMed Abstract: Human Diphtheria toxin-like ADP-ribosyltranferases (ARTD) 10 is an enzyme carrying out mono-ADP-ribosylation of a range of cellular proteins and affecting their activities. It shuttles between cytoplasm and nucleus and influences signaling events in both compartments, such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling and S phase DNA repair. Furthermore, overexpression of ARTD10 induces cell death. We recently reported on the discovery of a hit compound, OUL35 (compound 1), with 330 nM potency and remarkable selectivity towards ARTD10 over other enzymes in the human protein family. Here we aimed at establishing a structure-activity relationship of the OUL35 scaffold, by evaluating an array of 4-phenoxybenzamide derivatives. By exploring modifications on the linker between the aromatic rings, we identified also a 4-(benzyloxy)benzamide derivative, compound 32, which is potent (IC = 230 nM) and selective, and like OUL35 was able to rescue HeLa cells from ARTD10-induced cell death. Evaluation of an enlarged series of derivatives produced detailed knowledge on the structural requirements for ARTD10 inhibition and allowed the discovery of further tool compounds with submicromolar cellular potency that will help in understanding the roles of ARTD10 in biological systems.

PubMed: 30006177
DOI: 10.1016/j.ejmech.2018.06.047

Experimental method

X-RAY DIFFRACTION (1.6 Å)