4L6Z

Human artd3 (parp3) - catalytic domain in complex with inhibitor STO1168

4L6Z の概要

• エントリーDOI: 10.2210/pdb4l6z/pdb
• 関連するPDBエントリー: 4GV0 4GV2 4GV4 4L70 4L7L 4L7N 4L7O 4L7P 4L7R 4L7U
• 分子名称: Poly [ADP-ribose] polymerase 3, 3-(4-oxo-3,4-dihydroquinazolin-2-yl)-N-[(1S)-1-(pyridin-4-yl)ethyl]propanamide, DIMETHYL SULFOXIDE, ... (4 entities in total)
• 機能のキーワード: diphtheria toxin like adp-ribose transferase, transferase, adp-ribosylation, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus: Q9Y6F1
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 40152.57

構造登録者

Karlberg, T.,Thorsell, A.G.,Lindgren, A.E.G.,Ekblad, T.,Spjut, S.,Andersson, C.D.,Weigelt, J.,Linusson, A.,Elofsson, M.,Schuler, H. (登録日: 2013-06-13, 公開日: 2014-02-19, 最終更新日: 2023-09-20)

主引用文献

Lindgren, A.E.,Karlberg, T.,Ekblad, T.,Spjut, S.,Thorsell, A.G.,Andersson, C.D.,Nhan, T.T.,Hellsten, V.,Weigelt, J.,Linusson, A.,Schuler, H.,Elofsson, M.
Chemical Probes to Study ADP-Ribosylation: Synthesis and Biochemical Evaluation of Inhibitors of the Human ADP-Ribosyltransferase ARTD3/PARP3.
J.Med.Chem., 56:9556-9568, 2013

PubMed Abstract: The racemic 3-(4-oxo-3,4-dihydroquinazolin-2-yl)-N-[1-(pyridin-2-yl)ethyl]propanamide, 1, has previously been identified as a potent but unselective inhibitor of diphtheria toxin-like ADP-ribosyltransferase 3 (ARTD3). Herein we describe synthesis and evaluation of 55 compounds in this class. It was found that the stereochemistry is of great importance for both selectivity and potency and that substituents on the phenyl ring resulted in poor solubility. Certain variations at the meso position were tolerated and caused a large shift in the binding pose. Changes to the ethylene linker that connects the quinazolinone to the amide were also investigated but proved detrimental to binding. By combination of synthetic organic chemistry and structure-based design, two selective inhibitors of ARTD3 were discovered.

PubMed: 24188023
DOI: 10.1021/jm401394u

実験手法

X-RAY DIFFRACTION (2 Å)