3OY3

Crystal structure of ABL T315I mutant kinase domain bound with a DFG-out inhibitor AP24589

3OY3 の概要

• エントリーDOI: 10.2210/pdb3oy3/pdb
• 関連するPDBエントリー: 3IK3 3OXZ
• 分子名称: Tyrosine-protein kinase ABL1, 5-[(5-{[4-{[4-(2-hydroxyethyl)piperazin-1-yl]methyl}-3-(trifluoromethyl)phenyl]carbamoyl}-2-methylphenyl)ethynyl]-1-methyl-1H-imidazole-2-carboxamide (3 entities in total)
• 機能のキーワード: protein-inhibitor complex, protein kinase two-domain fold, phosphotransferase, atp binding, phosphorylation, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 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: 66756.16

構造登録者

Zhou, T.,Commodore, L.,Huang, W.S.,Wang, Y.,Thomas, M.,Keats, J.,Xu, Q.,Rivera, V.,Shakespeare, W.C.,Clackson, T.,Dalgarno, D.C.,Zhu, X. (登録日: 2010-09-22, 公開日: 2010-12-15, 最終更新日: 2023-09-06)

主引用文献

Zhou, T.,Commodore, L.,Huang, W.S.,Wang, Y.,Thomas, M.,Keats, J.,Xu, Q.,Rivera, V.M.,Shakespeare, W.C.,Clackson, T.,Dalgarno, D.C.,Zhu, X.
Structural Mechanism of the Pan-BCR-ABL Inhibitor Ponatinib (AP24534): Lessons for Overcoming Kinase Inhibitor Resistance.
Chem.Biol.Drug Des., 77:1-11, 2011

PubMed Abstract: The BCR-ABL inhibitor imatinib has revolutionized the treatment of chronic myeloid leukemia. However, drug resistance caused by kinase domain mutations has necessitated the development of new mutation-resistant inhibitors, most recently against the T315I gatekeeper residue mutation. Ponatinib (AP24534) inhibits both native and mutant BCR-ABL, including T315I, acting as a pan-BCR-ABL inhibitor. Here, we undertook a combined crystallographic and structure-activity relationship analysis on ponatinib to understand this unique profile. While the ethynyl linker is a key inhibitor functionality that interacts with the gatekeeper, virtually all other components of ponatinib play an essential role in its T315I inhibitory activity. The extensive network of optimized molecular contacts found in the DFG-out binding mode leads to high potency and renders binding less susceptible to disruption by single point mutations. The inhibitory mechanism exemplified by ponatinib may have broad relevance to designing inhibitors against other kinases with mutated gatekeeper residues.

PubMed: 21118377
DOI: 10.1111/j.1747-0285.2010.01054.x

実験手法

X-RAY DIFFRACTION (1.95 Å)