A monovalent agonist of TrkA tyrosine kinase receptors can be converted into a bivalent antagonist
A monovalent agonist of TrkA tyrosine kinase receptors can be converted into a bivalent antagonist
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DOI：
10.1016/j.bbagen.2010.06.007
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发表时间：
2010-09-01
影响因子：
3
通讯作者：
Saragovi, H. Uri
中科院分区：
文献类型：
--
作者：
Brahimi, Fouad;Liu, Jing;Saragovi, H. Uri
背景：受体酪氨酸激酶（RTK）通过二聚化作用。以前认为只有二价配体具有拮抗作用，而单价配体具有拮抗作用。在证明单价配体可以激动剂之后，这一概念发生了变化，包括我们报道的一种小分子单价配体“D3”是NGF受体TrkA的部分激动剂。二价“d3 -连接剂- d3”有望增加激动作用。方法：合成二聚体类似物，并进行结合、生化和生物检测。结果：一种类似物1-ss与TrkA结合的亲和力高于D3，诱导或稳定受体二聚体。然而，1-ss通过两种机制表现出拮抗活性。一种机制是1-ss阻断NGF结合，不像D3是非竞争性的。抑制NGF的结合可能是由于1-ss连接体填充了NGF对接前穿过的受体间空间。在第二种机制中，1-ss作为纯拮抗剂，抑制过表达受体细胞中不依赖ngf的TrkA活性。抑制可能是由于1-ss将TrkA二聚体“冻结”在非活性状态。结论：RTK的二聚化可通过两种独立的机制导致拮抗。一般意义：我们报告了一种小分子单价激动剂转化为二价拮抗剂。(C) 2010 Elsevier B.V.版权所有
Background: Receptor tyrosine kinases (RTK) act through dimerization. Previously it was thought that only bivalent ligands could be agonistic, whereas monovalent ligands should be antagonistic. This notion changed after the demonstration that monovalent ligands can be agonistic, including our report of a small molecule monovalent ligand "D3" that is a partial agonist of the NGF receptor TrkA. A bivalent "D3-linker-D3" was expected to increase agonism.Methods: Dimeric analogs were synthesized and tested in binding, biochemical, and biological assays.Results: One analog, 1-ss, binds TrkA with higher affinity than D3 and induces or stabilizes receptor dimers. However, 1-ss exhibited antagonistic activity, through two mechanisms. One mechanism is that 1-ss blocks NGF binding, unlike D3 which is non-competitive. Inhibition of NGF binding may be due to the linker of 1-ss filling the inter-receptor space that NGF traverses before docking. In a second mechanism, 1-ss acts as a pure antagonist, inhibiting NGF-independent TrkA activity in cells over-expressing receptors. Inhibition is likely due to 1-ss "freezing" the TrkA dimer in the inactive state.Conclusions: Dimerization of an RTK can result in antagonism, through two independent mechanisms.General significance: we report a small molecule monovalent agonist being converted to a bivalent antagonist. (C) 2010 Elsevier B.V. All rights reserved.