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Crystal Structure of the T315I Mutant of Abl Kinase
Author(s) -
Zhou Tianjun,
Parillon Lois,
Li Feng,
Wang Yihan,
Keats Jeff,
Lamore Sarah,
Xu Qihong,
Shakespeare William,
Dalgarno David,
Zhu Xiaotian
Publication year - 2007
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2007.00556.x
Subject(s) - nilotinib , dasatinib , protein kinase domain , imatinib , tyrosine kinase , mutant , myeloid leukemia , chemistry , mutation , kinase , cancer research , biology , biochemistry , signal transduction , gene
Imatinib (Gleevec) is currently the frontline therapy for chronic myeloid leukemia (CML), a disease characterized by the presence of a constitutively activated chimeric tyrosine kinase protein Bcr‐Abl. However, drug resistance often occurs at later stages of the disease, principally because of the occurrence of mutations in the kinase domain. Second generation Bcr‐Abl inhibitors, such as dasatinib and nilotinib are capable of inhibiting many imatinib‐resistant forms of the kinase but not the form in which threonine is mutated to isoleucine at the gatekeeper position (T315I). In this study, we present the crystal structure of the kinase domain of the c‐Abl T315I mutant, as well as the wild‐type form, in complex with a pyrrolopyridine inhibitor, PPY‐A. The side chain of Ile315 is accommodated in the Abl T315I mutant structure without large conformational changes proximal to the site of mutation. In contrast to other inhibitors, such as imatinib and dasatinib, PPY‐A does not occupy the hydrophobic pocket behind the gatekeeper residue. This binding mode, coupled with augmented contacts with the glycine‐rich loop, appears to be critical for its ability to override the T315I mutation. The data presented here may provide structural guidance for the design of clinically useful inhibitors of Bcr‐Abl T315I.