2F4J

Structure of the Kinase Domain of an Imatinib-Resistant Abl Mutant in Complex with the Aurora Kinase Inhibitor VX-680

2F4J の概要

• エントリーDOI: 10.2210/pdb2f4j/pdb
• 分子名称: Proto-oncogene tyrosine-protein kinase ABL1, CYCLOPROPANECARBOXYLIC ACID {4-[4-(4-METHYL-PIPERAZIN-1-YL)-6-(5-METHYL-2H-PYRAZOL-3-YLAMINO)-PYRIMIDIN-2-YLSULFANYL]-PHENYL}-AMIDE (3 entities in total)
• 機能のキーワード: kinase, kinase inhibitor, abl, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 33636.52

構造登録者

Young, M.A.,Shah, N.P.,Chao, L.H.,Zarrinkar, P.,Sawyers, P.,Kuriyan, J. (登録日: 2005-11-23, 公開日: 2006-01-24, 最終更新日: 2023-08-23)

主引用文献

Young, M.A.,Shah, N.P.,Chao, L.H.,Seeliger, M.,Milanov, Z.V.,Biggs, W.H.,Treiber, D.K.,Patel, H.K.,Zarrinkar, P.P.,Lockhart, D.J.,Sawyers, C.L.,Kuriyan, J.
Structure of the kinase domain of an imatinib-resistant Abl mutant in complex with the Aurora kinase inhibitor VX-680.
Cancer Res., 66:1007-1014, 2006

PubMed Abstract: We present a high-resolution (2.0 A) crystal structure of the catalytic domain of a mutant form of the Abl tyrosine kinase (H396P; Abl-1a numbering) that is resistant to the Abl inhibitor imatinib. The structure is determined in complex with the small-molecule inhibitor VX-680 (Vertex Pharmaceuticals, Cambridge, MA), which blocks the activity of various imatinib-resistant mutant forms of Abl, including one (T315I) that is resistant to both imatinib and BMS-354825 (dasatinib), a dual Src/Abl inhibitor that seems to be clinically effective against all other imatinib-resistant forms of BCR-Abl. VX-680 is shown to have significant inhibitory activity against BCR-Abl bearing the T315I mutation in patient-derived samples. The Abl kinase domain bound to VX-680 is not phosphorylated on the activation loop in the crystal structure but is nevertheless in an active conformation, previously unobserved for Abl and inconsistent with the binding of imatinib. The adoption of an active conformation is most likely the result of synergy between the His(396)Pro mutation, which destabilizes the inactive conformation required for imatinib binding, and the binding of VX-680, which favors the active conformation through hydrogen bonding and steric effects. VX-680 is bound to Abl in a mode that accommodates the substitution of isoleucine for threonine at residue 315 (the "gatekeeper" position). The avoidance of the innermost cavity of the Abl kinase domain by VX-680 and the specific recognition of the active conformation explain the effectiveness of this compound against mutant forms of BCR-Abl, including those with mutations at the gatekeeper position.

PubMed: 16424036
DOI: 10.1158/0008-5472.CAN-05-2788

実験手法

X-RAY DIFFRACTION (1.91 Å)