2VRX

Structure of Aurora B kinase in complex with ZM447439

2VRX の概要

• エントリーDOI: 10.2210/pdb2vrx/pdb
• 関連するPDBエントリー: 2BFX 2BFY 2VGO 2VGP
• 分子名称: SERINE/THREONINE-PROTEIN KINASE 12-A, INNER CENTROMERE PROTEIN A, N-(4-{[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]amino}phenyl)benzamide, ... (4 entities in total)
• 機能のキーワード: serine/threonine-protein kinase, kinase, nucleus, mitosis, magnesium, cell cycle/transferase, centromere, microtubule, atp-binding, transferase, anti-cancer drug target, phosphoprotein, protein kinase, nucleotide-binding, coiled coil, cell division, metal-binding, cell cycle-transferase complex
• 由来する生物種: XENOPUS LAEVIS (AFRICAN CLAWED FROG); 詳細
• 細胞内の位置: Nucleus: Q6DE08; Chromosome, centromere: O13024
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 78284.39

構造登録者

Girdler, F.,Sessa, F.,Patercoli, S.,Villa, F.,Ridgway, E.,Musacchio, A.,Taylor, S.S. (登録日: 2008-04-16, 公開日: 2008-07-01, 最終更新日: 2024-10-16)

主引用文献

Girdler, F.,Sessa, F.,Patercoli, S.,Villa, F.,Musacchio, A.,Taylor, S.S.
Molecular Basis of Drug Resistance in Aurora Kinases.
Chem.Biol., 15:552-, 2008

PubMed Abstract: Aurora kinases have emerged as potential targets in cancer therapy, and several drugs are currently undergoing preclinical and clinical validation. Whether clinical resistance to these drugs can arise is unclear. We exploited a hypermutagenic cancer cell line to select mutations conferring resistance to a well-studied Aurora inhibitor, ZM447439. All resistant clones contained dominant point mutations in Aurora B. Three mutations map to residues in the ATP-binding pocket that are distinct from the "gatekeeper" residue. The mutants retain wild-type catalytic activity and were resistant to all of the Aurora inhibitors tested. Our studies predict that drug-resistant Aurora B mutants are likely to arise during clinical treatment. Furthermore, because the plasticity of the ATP-binding pocket renders Aurora B insensitive to multiple inhibitors, our observations indicate that the drug-resistant Aurora B mutants should be exploited as novel drug targets.

PubMed: 18559266
DOI: 10.1016/J.CHEMBIOL.2008.04.013

実験手法

X-RAY DIFFRACTION (1.86 Å)