4WA9

The crystal structure of human abl1 wild type kinase domain in complex with axitinib

4WA9 の概要

• エントリーDOI: 10.2210/pdb4wa9/pdb
• 分子名称: Tyrosine-protein kinase ABL1, AXITINIB (3 entities in total)
• 機能のキーワード: kinase, kinase inhibitor, axitinib, activation loop, dfg-out, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm, cytoskeleton. Isoform IB: Nucleus membrane; Lipid-anchor: P00519
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 66854.39

構造登録者

Johnson, E.,McTigue, M.,Cronin, C.N. (登録日: 2014-08-28, 公開日: 2015-02-11, 最終更新日: 2024-08-07)

主引用文献

Pemovska, T.,Johnson, E.,Kontro, M.,Repasky, G.A.,Chen, J.,Wells, P.,Cronin, C.N.,McTigue, M.,Kallioniemi, O.,Porkka, K.,Murray, B.W.,Wennerberg, K.
Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation.
Nature, 519:102-105, 2015

PubMed Abstract: The BCR-ABL1 fusion gene is a driver oncogene in chronic myeloid leukaemia and 30-50% of cases of adult acute lymphoblastic leukaemia. Introduction of ABL1 kinase inhibitors (for example, imatinib) has markedly improved patient survival, but acquired drug resistance remains a challenge. Point mutations in the ABL1 kinase domain weaken inhibitor binding and represent the most common clinical resistance mechanism. The BCR-ABL1 kinase domain gatekeeper mutation Thr315Ile (T315I) confers resistance to all approved ABL1 inhibitors except ponatinib, which has toxicity limitations. Here we combine comprehensive drug sensitivity and resistance profiling of patient cells ex vivo with structural analysis to establish the VEGFR tyrosine kinase inhibitor axitinib as a selective and effective inhibitor for T315I-mutant BCR-ABL1-driven leukaemia. Axitinib potently inhibited BCR-ABL1(T315I), at both biochemical and cellular levels, by binding to the active form of ABL1(T315I) in a mutation-selective binding mode. These findings suggest that the T315I mutation shifts the conformational equilibrium of the kinase in favour of an active (DFG-in) A-loop conformation, which has more optimal binding interactions with axitinib. Treatment of a T315I chronic myeloid leukaemia patient with axitinib resulted in a rapid reduction of T315I-positive cells from bone marrow. Taken together, our findings demonstrate an unexpected opportunity to repurpose axitinib, an anti-angiogenic drug approved for renal cancer, as an inhibitor for ABL1 gatekeeper mutant drug-resistant leukaemia patients. This study shows that wild-type proteins do not always sample the conformations available to disease-relevant mutant proteins and that comprehensive drug testing of patient-derived cells can identify unpredictable, clinically significant drug-repositioning opportunities.

PubMed: 25686603
DOI: 10.1038/nature14119

実験手法

X-RAY DIFFRACTION (2.2 Å)