ATP-site inhibitors induce unique conformations of the acute myeloid leukemia-associated Src-family kinase, Fgr.
ATP-site inhibitors induce unique conformations of the acute myeloid leukemia-associated Src-family kinase, Fgr.
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DOI：
10.1016/j.str.2022.08.008
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发表时间：
2022-11-03
期刊：
影响因子：
5.7
通讯作者：
Smithgall, Thomas E.
中科院分区：
文献类型：
--
作者：
Du, Shoucheng;Alvarado, John J.;Wales, Thomas E.;Moroco, Jamie A.;Engen, John R.;Smithgall, Thomas E.
Src家族激酶Fgr主要在髓系造血细胞中表达，并导致髓系白血病。在这里，我们提出的X-射线晶体结构的FGR绑定到ATP位点抑制剂A-419259和TL 02 -59，这显示出作为抗白血病药物的前景。A-419259诱导闭合Fgr构象，其中SH 3和SH 2结构域分别接合SH 2激酶接头和C末端尾。在二聚体Fgr：A-419259复合物中，一个单体的激活环插入另一个单体的活性位点，提供了反式自磷酸化的快照。相比之下，TL 02 -59结合诱导SH 2结构域从C-末端尾置换和SH 3结构域从接头释放。使用HDX MS的溶液研究与晶体结构一致，其中A-419259减少和TL 02 -59增强SH 3结构域的溶剂暴露。这些结构表明，Src家族激酶的激酶和调节结构域之间的变构连接由与活性位点结合的配体调节。Fgr蛋白酪氨酸激酶参与髓系白血病的发展。模块SH 3和SH 2结构域与Fgr激酶结构域相互作用以调节功能。Du等人提出了与不同ATP位点抑制剂结合的Fgr的晶体结构，其揭示了对整体激酶构象的相反变构效应。
The Src-family kinase Fgr is expressed primarily in myeloid hematopoietic cells and contributes to myeloid leukemia. Here, we present X-ray crystal structures of Fgr bound to the ATP-site inhibitors A-419259 and TL02–59, which show promise as anti-leukemic agents. A-419259 induces a closed Fgr conformation, with the SH3 and SH2 domains engaging the SH2-kinase linker and C-terminal tail, respectively. In the dimeric Fgr:A-419259 complex, the activation loop of one monomer inserts into the active site of the other, providing a snapshot of trans-autophosphorylation. By contrast, TL02–59 binding induced SH2 domain displacement from the C-terminal tail and SH3 domain release from the linker. Solution studies using HDX MS were consistent with the crystal structures, with A-419259 reducing and TL02–59 enhancing solvent exposure of the SH3 domain. These structures demonstrate that allosteric connections between the kinase and regulatory domains of Src-family kinases are regulated by the ligand bound to the active site. The Fgr protein-tyrosine kinase contributes to the development of myeloid leukemia. Modular SH3 and SH2 domains interact with the Fgr kinase domain to regulate function. Du et al. present crystal structures of Fgr bound to distinct ATP-site inhibitors, which reveal opposing allosteric effects on the overall kinase conformation.
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影响因子：
14.9
作者：
Perez-Riverol Y;Bai J;Bandla C;García-Seisdedos D;Hewapathirana S;Kamatchinathan S;Kundu DJ;Prakash A;Frericks-Zipper A;Eisenacher M;Walzer M;Wang S;Brazma A;Vizcaíno JA
通讯作者：
Vizcaíno JA
影响因子：
48
作者：
Masson, Glenn R.;Burke, John E.;Rand, Kasper D.
通讯作者：
Rand, Kasper D.
影响因子：
14.8
作者：
Mueller, Susanne;Chaikuad, Apirat;Knapp, Stefan
通讯作者：
Knapp, Stefan
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
17.1
作者：
Saito, Yoriko;Yuki, Hitomi;Ishikawa, Fumihiko
通讯作者：
Ishikawa, Fumihiko