4GV4

Human ARTD3 (PARP3) - Catalytic domain in complex with inhibitor ME0328

Summary for 4GV4

• Entry DOI: 10.2210/pdb4gv4/pdb
• Related: 4GV0 4GV2
• Descriptor: Poly [ADP-ribose] polymerase 3, 3-(4-oxo-3,4-dihydroquinazolin-2-yl)-N-[(1S)-1-phenylethyl]propanamide, DIMETHYL SULFOXIDE, ... (4 entities in total)
• Functional Keywords: nad, adp-ribose, parp3, artd3, artd transferase domain, adp- ribosylation, transferase-transferase inhibitor complex, transferase, adp-ribosylation, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: Q9Y6F1
• Total number of polymer chains: 1
• Total formula weight: 40151.58

Authors

Karlberg, T.,Thorsell, A.G.,Lindgren, A.E.G.,Ekblad, T.,Spjut, S.,Andersson, C.D.,Weigelt, J.,Linusson, A.,Elofsson, M.,Schuler, H. (deposition date: 2012-08-30, release date: 2013-06-19, Last modification date: 2023-11-08)

Primary citation

Lindgren, A.E.G.,Karlberg, T.,Thorsell, A.G.,Hesse, M.,Spjut, S.,Ekblad, T.,Andersson, C.D.,Pinto, A.F.,Weigelt, J.,Hottiger, M.O.,Linusson, A.,Elofsson, M.,Schuler, H.
PARP Inhibitor with Selectivity Toward ADP-Ribosyltransferase ARTD3/PARP3
Acs Chem.Biol., 8:1698-1703, 2013

PubMed Abstract: Inhibiting ADP-ribosyl transferases with PARP-inhibitors is considered a promising strategy for the treatment of many cancers and ischemia, but most of the cellular targets are poorly characterized. Here, we describe an inhibitor of ADP-ribosyltransferase-3/poly(ADP-ribose) polymerase-3 (ARTD3), a regulator of DNA repair and mitotic progression. In vitro profiling against 12 members of the enzyme family suggests selectivity for ARTD3, and crystal structures illustrate the molecular basis for inhibitor selectivity. The compound is active in cells, where it elicits ARTD3-specific effects at submicromolar concentration. Our results show that by targeting the nicotinamide binding site, selective inhibition can be achieved among the closest relatives of the validated clinical target, ADP-ribosyltransferase-1/poly(ADP-ribose) polymerase-1.

PubMed: 23742272
DOI: 10.1021/cb4002014

Experimental method

X-RAY DIFFRACTION (1.8 Å)