Structural insights into the inhibited states of the Mer receptor tyrosine kinase.
Structural insights into the inhibited states of the Mer receptor tyrosine kinase.
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DOI：
10.1016/j.jsb.2008.10.003
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发表时间：
2009-02
影响因子：
3
通讯作者：
Dhe-Paganon, Sirano
中科院分区：
文献类型：
--
作者：
Huang, Xudong;Finerty, Patrick, Jr.;Walker, John R.;Butler-Cole, Christine;Vedadi, Masoud;Schapira, Matthieu;Parker, Sirlester A.;Turk, Benjamin E.;Thompson, Debra A.;Dhe-Paganon, Sirano
逆转录病毒癌基因v-Eyk的哺乳动物直系同源物，以及抗凋亡和转化信号上游的受体酪氨酸激酶，Mer（MerTK）是吞噬过程的介体，参与视网膜和免疫细胞清除以及血小板聚集。Mer基因敲除小鼠是可行的，并保护肾上腺素诱导的肺血栓栓塞和氯化铁诱导的血栓形成。另一方面，Mer过表达与许多癌相关。虽然已经鉴定了Mer衔接蛋白和信号通路，但仍不清楚Mer如何启动吞噬作用。当与其核苷酸辅因子结合时，Mer的高分辨率结构显示出自抑制的αC-Glu-out构象，并在活性位点插入激活环残基。Mer与化合物-52（C52：2-（2-羟乙基氨基）-6-（3-氯苯胺基）-9-异丙基嘌呤）（从聚焦文库中鉴定的配体）复合，保留其DFG-Asp-in和αC-Glu-out构象，但获得其他构象变化。αC螺旋和DFGL区域更靠近铰链区，C52的乙醇胺部分结合在P环的Leu 593和Val 601之间形成的凹槽中，导致活性位点口袋的压缩。这些构象状态揭示了自抑制的机制，致病突变的病理生理基础，以及化学探针的发展平台。
The mammalian ortholog of the retroviral oncogene v-Eyk, and a receptor tyrosine kinase upstream of antiapoptotic and transforming signals, Mer (MerTK) is a mediator of the phagocytic process, being involved in retinal and immune cell clearance and platelet aggregation. Mer knockout mice are viable and are protected from epinephrine-induced pulmonary thromboembolism and ferric chloride-induced thrombosis. Mer overexpression, on the other hand, is associated with numerous carcinomas. Although Mer adaptor proteins and signaling pathways have been identified, it remains unclear how Mer initiates phagocytosis. When bound to its nucleotide cofactor, the high-resolution structure of Mer shows an autoinhibited αC-Glu-out conformation with insertion of an activation loop residue into the active site. Mer complexed with compound-52 (C52: 2-(2-hydroxyethylamino)-6-(3-chloroanilino)-9-isopropylpurine), a ligand identified from a focused library, retains its DFG-Asp-in and αC-Glu-out conformation, but acquires other conformational changes. The αC helix and DFGL region is closer to the hinge region and the ethanolamine moiety of C52 binds in the groove formed between Leu593 and Val601 of the P-loop, causing a compression of the active site pocket. These conformational states reveal the mechanisms of autoinhibition, the pathophysiological basis of disease-causing mutations, and a platform for the development of chemical probes.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
30.8
作者：
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通讯作者：
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DOI：
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发表时间：
2002-12-20
影响因子：
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作者：
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通讯作者：
Dahlbäck, B
影响因子：
8
作者：
Chen, J;Carey, K;Godowski, PJ
通讯作者：
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DOI：
10.1161/01.atv.0000130662.30537.08
发表时间：
2004-06-01
影响因子：
8.7
作者：
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通讯作者：
Damiano, BP