5LYH
Human PARP14 (ARTD8), catalytic fragment in complex with inhibitor H10
Summary for 5LYH
Entry DOI | 10.2210/pdb5lyh/pdb |
Related | 5LXP |
Descriptor | Poly [ADP-ribose] polymerase 14, 3-[2-[4-[2-[[4-[(3-aminocarbonylphenyl)amino]-4-oxidanylidene-butanoyl]amino]ethyl]-1,2,3-triazol-1-yl]ethylsulfamoyl]benzoic acid (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 | 45352.34 |
Authors | Karlberg, T.,Thorsell, A.G.,Schuler, H. (deposition date: 2016-09-28, release date: 2016-12-21, Last modification date: 2024-11-06) |
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 Cited by 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: 27918638DOI: 10.1002/anie.201609655 PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (2.17 Å) |
Structure validation
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