A Src-like inactive conformation in the abl tyrosine kinase domain.
A Src-like inactive conformation in the abl tyrosine kinase domain.
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ABL酪氨酸激酶结构域中的SRC样不活跃构象。
DOI：
10.1371/journal.pbio.0040144
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发表时间：
2006-05
期刊：
影响因子：
9.8
通讯作者：
Kuriyan J
中科院分区：
文献类型：
--
作者：
Levinson NM;Kuchment O;Shen K;Young MA;Koldobskiy M;Karplus M;Cole PA;Kuriyan J
Abl酪氨酸激酶的异常激活导致慢性粒细胞白血病(CML)。Abl的非活性构象的识别，其中一个催化重要的Asp-Phe-Gly(DFG)基序相对于活性构象翻转了约180°，这奠定了用于治疗CML的抗癌药物伊马替尼的特异性。DFG基序在密切相关的Src激酶的非活性形式的晶体结构中没有翻转，伊马替尼也不抑制c-Src。我们提出了一种Abl激活域的结构，该结构是在与ATP-多肽结合物的复合体中确定的，其中蛋白质采用了与Src激酶非常相似的非活性构象。分子动力学模拟和额外的晶体结构表明，类Src非活性结构的一个有趣方面是存在一些特征，这些特征可能有助于DFG基序的翻转，因为它为苯丙氨酸提供了移动的空间，并在苯丙氨酸离开活性中心时协调了天冬氨酸侧链。BCR-Abl中一类对伊马替尼具有耐药性的突变似乎比活性构象或伊马替尼结合的构象更有可能破坏非活性的类似Src的构象的稳定。我们的结果表明，不同的非活性构象之间的相互转换是Abl激酶域的一个特征。SRC-和Abl-激酶被认为具有不同的非活性构象，这是用于治疗慢性髓细胞白血病的药物伊曼替尼的不同反应的原因。然而，在这里，Abl-Kinase也具有类似于Src的构象状态。
The improper activation of the Abl tyrosine kinase results in chronic myeloid leukemia (CML). The recognition of an inactive conformation of Abl, in which a catalytically important Asp-Phe-Gly (DFG) motif is flipped by approximately 180° with respect to the active conformation, underlies the specificity of the cancer drug imatinib, which is used to treat CML. The DFG motif is not flipped in crystal structures of inactive forms of the closely related Src kinases, and imatinib does not inhibit c-Src. We present a structure of the kinase domain of Abl, determined in complex with an ATP–peptide conjugate, in which the protein adopts an inactive conformation that resembles closely that of the Src kinases. An interesting aspect of the Src-like inactive structure, suggested by molecular dynamics simulations and additional crystal structures, is the presence of features that might facilitate the flip of the DFG motif by providing room for the phenylalanine to move and by coordinating the aspartate side chain as it leaves the active site. One class of mutations in BCR–Abl that confers resistance to imatinib appears more likely to destabilize the inactive Src-like conformation than the active or imatinib-bound conformations. Our results suggest that interconversion between distinctly different inactive conformations is a characteristic feature of the Abl kinase domain. Src- and Abl-kinases are thought to have distinct inactive conformations, accounting for differential responses to the drug imantinib, used to treat chronic myeloid leukemia. Here, however, Abl-kinases are shown to also have Src-like conformational states.
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影响因子：
64.5
作者：
Azam, M;Latek, RR;Daley, GQ
通讯作者：
Daley, GQ
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11.4
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Hubbard, SR
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Hubbard, SR
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BURLEY, SK;PETSKO, GA
通讯作者：
PETSKO, GA
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Apperley, JF;Gardembas, M;Goldman, JM
通讯作者：
Goldman, JM
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作者：
BROOKS, BR;BRUCCOLERI, RE;KARPLUS, M
通讯作者：
KARPLUS, M