3H0Z

Aurora A in complex with a bisanilinopyrimidine

3H0Z の概要

• エントリーDOI: 10.2210/pdb3h0z/pdb
• 関連するPDBエントリー: 3COH 3H0Y 3H10
• 分子名称: Serine/threonine-protein kinase 6, 4-{[2-({4-[2-(4-acetylpiperazin-1-yl)-2-oxoethyl]phenyl}amino)-5-fluoropyrimidin-4-yl]amino}-N-(2-chlorophenyl)benzamide (2 entities in total)
• 機能のキーワード: protein:inhibitor complex aurora-a, cell cycle, serine/threonine, protein kinase, atp-binding, kinase, nucleotide-binding, phosphoprotein, serine/threonine-protein kinase, transferase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm, cytoskeleton, centrosome: O14965
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 94949.34

構造登録者

Wiesmann, C.,Ultsch, M.H.,Cochran, A.G. (登録日: 2009-04-10, 公開日: 2009-07-07, 最終更新日: 2024-02-21)

主引用文献

Aliagas-Martin, I.,Burdick, D.,Corson, L.,Dotson, J.,Drummond, J.,Fields, C.,Huang, O.W.,Hunsaker, T.,Kleinheinz, T.,Krueger, E.,Liang, J.,Moffat, J.,Phillips, G.,Pulk, R.,Rawson, T.E.,Ultsch, M.,Walker, L.,Wiesmann, C.,Zhang, B.,Zhu, B.Y.,Cochran, A.G.
A class of 2,4-bisanilinopyrimidine Aurora A inhibitors with unusually high selectivity against Aurora B.
J.Med.Chem., 52:3300-3307, 2009

PubMed Abstract: The two major Aurora kinases carry out critical functions at distinct mitotic stages. Selective inhibitors of these kinases, as well as pan-Aurora inhibitors, show antitumor efficacy and are now under clinical investigation. However, the ATP-binding sites of Aurora A and Aurora B are virtually identical, and the structural basis for selective inhibition has therefore not been clear. We report here a class of bisanilinopyrimidine Aurora A inhibitors with excellent selectivity for Aurora A over Aurora B, both in enzymatic assays and in cellular phenotypic assays. Crystal structures of two of the inhibitors in complex with Aurora A implicate a single amino acid difference in Aurora B as responsible for poor inhibitory activity against this enzyme. Mutation of this residue in Aurora B (E161T) or Aurora A (T217E) is sufficient to swap the inhibition profile, suggesting that this difference might be exploited more generally to achieve high selectivity for Aurora A.

PubMed: 19402633
DOI: 10.1021/jm9000314

実験手法

X-RAY DIFFRACTION (2.92 Å)