4UND

HUMAN ARTD1 (PARP1) - CATALYTIC DOMAIN IN COMPLEX WITH INHIBITOR TALAZOPARIB

4UND の概要

• エントリーDOI: 10.2210/pdb4und/pdb
• 分子名称: POLY [ADP-RIBOSE] POLYMERASE 1, (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one, SODIUM ION, ... (4 entities in total)
• 機能のキーワード: transferase, protein-inhibitor complex, adp-ribosylation, dna repair
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Nucleus: P09874
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 84501.17

構造登録者

Karlberg, T.,Thorsell, A.G.,Ekblad, T.,Klepsch, M.,Pinto, A.F.,Tresaugues, L.,Moche, M.,Schuler, H. (登録日: 2014-05-27, 公開日: 2015-06-17, 最終更新日: 2024-01-10)

主引用文献

Thorsell, A.G.,Ekblad, T.,Karlberg, T.,Low, M.,Pinto, A.F.,Tresaugues, L.,Moche, M.,Cohen, M.S.,Schuler, H.
Structural Basis for Potency and Promiscuity in Poly(ADP-ribose) Polymerase (PARP) and Tankyrase Inhibitors.
J. Med. Chem., 60:1262-1271, 2017

PubMed Abstract: Selective inhibitors could help unveil the mechanisms by which inhibition of poly(ADP-ribose) polymerases (PARPs) elicits clinical benefits in cancer therapy. We profiled 10 clinical PARP inhibitors and commonly used research tools for their inhibition of multiple PARP enzymes. We also determined crystal structures of these compounds bound to PARP1 or PARP2. Veliparib and niraparib are selective inhibitors of PARP1 and PARP2; olaparib, rucaparib, and talazoparib are more potent inhibitors of PARP1 but are less selective. PJ34 and UPF1069 are broad PARP inhibitors; PJ34 inserts a flexible moiety into hydrophobic subpockets in various ADP-ribosyltransferases. XAV939 is a promiscuous tankyrase inhibitor and a potent inhibitor of PARP1 in vitro and in cells, whereas IWR1 and AZ-6102 are tankyrase selective. Our biochemical and structural analysis of PARP inhibitor potencies establishes a molecular basis for either selectivity or promiscuity and provides a benchmark for experimental design in assessment of PARP inhibitor effects.

PubMed: 28001384
DOI: 10.1021/acs.jmedchem.6b00990

実験手法

X-RAY DIFFRACTION (2.2 Å)