A Deep Hydrophobic Binding Cavity is the Main Interaction for Different Y2R Antagonists
A Deep Hydrophobic Binding Cavity is the Main Interaction for Different Y2R Antagonists
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DOI：
10.1002/cmdc.201600433
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发表时间：
2017-01-05
期刊：
影响因子：
3.4
通讯作者：
Beck-Sickinger, Annette G.
中科院分区：
文献类型：
--
作者：
Burkert, Kerstin;Zellmann, Tristan;Beck-Sickinger, Annette G.
神经肽Y(2)受体(Y2R)参与癫痫、心境障碍、血管生成和肿瘤生长等多种病理生理过程。因此，Y2R是药物开发的一个有趣的目标。对结合口袋的详细了解有助于开发高度选择性的拮抗剂来研究Y2R体外和体内的作用。在本研究中，通过信号转导分析研究了BIIE0246和SF-11衍生物与Y2R相互作用的几个关键残基。以实验结果为约束，将拮抗剂对接到Y2R的比较结构模型中。尽管大小和结构不同，但这三种拮抗剂都显示了相似的结合部位，包括由跨膜螺旋(TM)4、5和6形成的深疏水空腔，以及TM2和7的顶部的疏水斑块。此外，我们认为拮抗剂阻断了Q(3.32)，这一位置已被证明对NPY的酰胺化末端结合从而对受体激活至关重要。
The neuropeptideY(2) receptor (Y2R) is involved in various pathophysiological processes such as epilepsy, mood disorders, angiogenesis, and tumor growth. Therefore, the Y2R is an interesting target for drug development. A detailed understanding of the binding pocket could facilitate the development of highly selective antagonists to study the role of Y2R invitro and invivo. In this study, several residues crucial to the interaction of BIIE0246 and SF-11 derivatives with Y2R were investigated by signal transduction assays. Using the experimental results as constraints, the antagonists were docked into a comparative structural model of the Y2R. Despite differences in size and structure, all three antagonists display a similar binding site, including a deep hydrophobic cavity formed by transmembrane helices (TM) 4, 5, and 6, as well as a hydrophobic patch at the top of TM2 and 7. Additionally, we suggest that the antagonists block Q(3.32), a position that has been shown to be crucial for binding of the amidated Cterminus of NPY and thus for receptor activation.