Structure of a GPCR Ligand in Its Receptor-Bound State: Leukotriene B4 Adopts a Highly Constrained Conformation When Associated to Human BLT2
Structure of a GPCR Ligand in Its Receptor-Bound State: Leukotriene B4 Adopts a Highly Constrained Conformation When Associated to Human BLT2
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DOI：
10.1021/ja101868c
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发表时间：
2010-07-07
影响因子：
15
通讯作者：
Baneres, Jean-Louis
中科院分区：
文献类型：
--
作者：
Catoire, Laurent J.;Damian, Marjorie;Baneres, Jean-Louis
G蛋白偶联受体（GPCR）是信号识别和细胞通讯的关键参与者，也是药物开发的最重要靶点之一。利用在大肠杆菌中以全氘代形式表达的白三烯受体BLT 2，以毫克量纯化，并使用Amphipol折叠到其天然状态，我们已经通过H-1 NMR解决了受体结合的白三烯B4（LTB 4）的结构。结合后，LTB 4采用高度受限的海马构象，与自由状态不同，它探索了广泛的构象。这种结构为进一步的药理学研究提供了实验确定的促炎化合物模板。用于其测定的新方法可能被证明对于研究配体与GPCR和膜蛋白的一般结合是强大的。
G protein-coupled receptors (GPCRs) are key players in signal recognition and cell communication and are among the most important targets for drug development. Direct structural information on the conformation of GPCR ligands bound to their receptors is scarce Using a leukotriene receptor, BLT2, expressed under a perdeuterated form in Escherichia colt, purified in milligram amounts, and folded to its native state using amphipols, we have solved, by H-1 NMR, the structure of receptor-bound leukotriene B4 (LTB4) Upon binding, LTB4 adopts a highly constrained seahorse conformation, at variance with the free state, where it explores a wide range of conformations. This structure provides an experimentally determined template of a pro-inflammatory compound for further pharmacological studies The novel approach used for its determination could prove powerful to investigate ligand binding to GPCRs and membrane proteins in general.