3K5V

Structure of Abl kinase in complex with imatinib and GNF-2

3K5V の概要

• エントリーDOI: 10.2210/pdb3k5v/pdb
• 関連するPDBエントリー: 1OPJ
• 分子名称: Tyrosine-protein kinase ABL1, 3-(6-{[4-(trifluoromethoxy)phenyl]amino}pyrimidin-4-yl)benzamide, 4-(4-METHYL-PIPERAZIN-1-YLMETHYL)-N-[4-METHYL-3-(4-PYRIDIN-3-YL-PYRIMIDIN-2-YLAMINO)-PHENYL]-BENZAMIDE, ... (5 entities in total)
• 機能のキーワード: kinase, atp-binding, nucleotide-binding, oncogene, sh2 domain, transferase, tyrosine-protein kinase
• 由来する生物種: Mus musculus (mouse)
• 細胞内の位置: Cytoplasm, cytoskeleton: P00520
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 69258.34

構造登録者

Cowan-Jacob, S.W.,Fendrich, G.,Rummel, G.,Strauss, A. (登録日: 2009-10-08, 公開日: 2010-01-19, 最終更新日: 2023-09-06)

主引用文献

Zhang, J.,Adrian, F.J.,Jahnke, W.,Cowan-Jacob, S.W.,Li, A.G.,Iacob, R.E.,Sim, T.,Powers, J.,Dierks, C.,Sun, F.,Guo, G.R.,Ding, Q.,Okram, B.,Choi, Y.,Wojciechowski, A.,Deng, X.,Liu, G.,Fendrich, G.,Strauss, A.,Vajpai, N.,Grzesiek, S.,Tuntland, T.,Liu, Y.,Bursulaya, B.,Azam, M.,Manley, P.W.,Engen, J.R.,Daley, G.Q.,Warmuth, M.,Gray, N.S.
Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors.
Nature, 463:501-506, 2010

PubMed Abstract: In an effort to find new pharmacological modalities to overcome resistance to ATP-binding-site inhibitors of Bcr-Abl, we recently reported the discovery of GNF-2, a selective allosteric Bcr-Abl inhibitor. Here, using solution NMR, X-ray crystallography, mutagenesis and hydrogen exchange mass spectrometry, we show that GNF-2 binds to the myristate-binding site of Abl, leading to changes in the structural dynamics of the ATP-binding site. GNF-5, an analogue of GNF-2 with improved pharmacokinetic properties, when used in combination with the ATP-competitive inhibitors imatinib or nilotinib, suppressed the emergence of resistance mutations in vitro, displayed additive inhibitory activity in biochemical and cellular assays against T315I mutant human Bcr-Abl and displayed in vivo efficacy against this recalcitrant mutant in a murine bone-marrow transplantation model. These results show that therapeutically relevant inhibition of Bcr-Abl activity can be achieved with inhibitors that bind to the myristate-binding site and that combining allosteric and ATP-competitive inhibitors can overcome resistance to either agent alone.

PubMed: 20072125
DOI: 10.1038/nature08675

実験手法

X-RAY DIFFRACTION (1.74 Å)