5LXP

Human PARP14 (ARTD8), catalytic fragment in complex with inhibitor H5

Summary for 5LXP

• Entry DOI: 10.2210/pdb5lxp/pdb
• Descriptor: Poly [ADP-ribose] polymerase 14, ~{N}'-(3-aminocarbonylphenyl)-~{N}-[[1-[(2~{R})-2-phenylpropyl]-1,2,3-triazol-4-yl]methyl]pentanediamide (3 entities in total)
• Functional Keywords: adp-ribosylation, inhibitor complex, transferase domain, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus: Q460N5
• Total number of polymer chains: 2
• Total formula weight: 45134.22

Authors

Karlberg, T.,Thorsell, A.G.,Schuler, H. (deposition date: 2016-09-22, release date: 2016-12-21, Last modification date: 2024-11-20)

Primary citation

Peng, B.,Thorsell, A.G.,Karlberg, T.,Schuler, H.,Yao, S.Q.
Small Molecule Microarray Based Discovery of PARP14 Inhibitors.
Angew. Chem. Int. Ed. Engl., 56:248-253, 2017

PubMed Abstract: Poly(ADP-ribose) polymerases (PARPs) are key enzymes in a variety of cellular processes. Most small-molecule PARP inhibitors developed to date have been against PARP1, and suffer from poor selectivity. PARP14 has recently emerged as a potential therapeutic target, but its inhibitor development has trailed behind. Herein, we describe a small molecule microarray-based strategy for high-throughput synthesis, screening of >1000 potential bidentate inhibitors of PARPs, and the successful discovery of a potent PARP14 inhibitor H10 with >20-fold selectivity over PARP1. Co-crystallization of the PARP14/H10 complex indicated H10 bound to both the nicotinamide and the adenine subsites. Further structure-activity relationship studies identified important binding elements in the adenine subsite. In tumor cells, H10 was able to chemically knockdown endogenous PARP14 activities.

PubMed: 27918638
DOI: 10.1002/anie.201609655

Experimental method

X-RAY DIFFRACTION (2.07 Å)