Predicted structure of agonist-bound glucagon-like peptide 1 receptor, a class B G protein-coupled receptor
Predicted structure of agonist-bound glucagon-like peptide 1 receptor, a class B G protein-coupled receptor
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DOI：
10.1073/pnas.1218051109
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发表时间：
2012-12-04
影响因子：
11.1
通讯作者：
Goddard, William A., III
中科院分区：
文献类型：
--
作者：
Kirkpatrick, Andrea;Heo, Jiyoung;Goddard, William A., III
胰高血糖素样肽1受体（glucagon-like peptide 1 receptor，GLP 1 R）是一种G蛋白偶联受体（G protein-coupled receptor，GPCR），参与胰岛素的合成和调节，是治疗糖尿病的重要药物靶点。然而，GLP 1 R是GPCR的B1类家族的成员，其没有实验结构。为了提供药物设计的结构基础和探测B类GPCR活化，我们使用用于扫描TM束构象的ESTRUK方法预测了与肽Exendin-4（Exe 4;市场上用于治疗糖尿病的GLP 1 R激动剂）结合的GLP 1 R的跨膜（TM）束结构。我们使用蛋白质-蛋白质对接方法将TM束与143-aa N末端偶联至Exe 4肽的X射线晶体结构联合收割机结合。该复合物进行28 ns的全溶剂，全脂质分子动力学。我们发现14个强极性相互作用的外显子4与GLP 1 R，其中8个相互作用是在TM束（突变研究证实的2个相互作用）和6个相互作用涉及的N端（3个相互作用中发现的晶体结构）。我们还发现了10个重要的疏水相互作用，其中4个相互作用是在TM束（突变研究证实的2个相互作用）和6个相互作用是在N端（6个相互作用存在于晶体结构）。因此，我们预测的结构与现有的诱变研究一致。我们建议一些突变实验，以进一步验证我们的预测结构。该结构应可用于指导药物设计，并可为理解GLP 1 R和其他B1类GPCR的配体结合和受体活化提供结构基础。
The glucagon-like peptide 1 receptor (GLP1R) is a G protein-coupled receptor (GPCR) involved in insulin synthesis and regulation; therefore, it is an important drug target for treatment of diabetes. However, GLP1R is a member of the class B1 family of GPCRs for which there are no experimental structures. To provide a structural basis for drug design and to probe class B GPCR activation, we predicted the transmembrane (TM) bundle structure of GLP1R bound to the peptide Exendin-4 (Exe4; a GLP1R agonist on the market for treating diabetes) using the MembStruk method for scanning TM bundle conformations. We used protein-protein docking methods to combine the TM bundle with the X-ray crystal structure of the 143-aa N terminus coupled to the Exe4 peptide. This complex was subjected to 28 ns of full-solvent, full-lipid molecular dynamics. We find 14 strong polar interactions of Exe4 with GLP1R, of which 8 interactions are in the TM bundle (2 interactions confirmed by mutation studies) and 6 interactions involve the N terminus (3 interactions found in the crystal structure). We also find 10 important hydrophobic interactions, of which 4 interactions are in the TM bundle (2 interactions confirmed by mutation studies) and 6 interactions are in the N terminus (6 interactions present in the crystal structure). Thus, our predicted structure agrees with available mutagenesis studies. We suggest a number of mutation experiments to further validate our predicted structure. The structure should be useful for guiding drug design and can provide a structural basis for understanding ligand binding and receptor activation of GLP1R and other class B1 GPCRs.