Modeled structure of a G-protein-coupled receptor: The Cholecystokinin-1 receptor
Modeled structure of a G-protein-coupled receptor: The Cholecystokinin-1 receptor
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DOI：
10.1021/jm049886y
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发表时间：
2005-01-13
影响因子：
7.3
通讯作者：
Fourmy, D
中科院分区：
文献类型：
--
作者：
Archer-Lahlou, E;Tikhonova, I;Fourmy, D
胆囊收缩素-1受体（CCK 1 R）介导CCK在中枢神经系统和肠道区域的作用。它是治疗许多疾病的潜在靶点。对于所有的G蛋白偶联受体，配体与模型CCK 1 R结合位点的对接将极大地有助于理解其内在的激活机制。在这里，我们描述了我们用于逐步构建CCK 1 R结构模型、整合并基于其结合位点的定点突变数据的程序。CCK 1 R模型的可靠性得到了证实的相互作用网络，涉及保守的和功能上至关重要的基序在G-蛋白偶联受体，如Glu/Asp-Arg-Tyr和Asn-Pro-Xaa-Xaa-Tyr基序。此外，CCK 1 R结合CCK的3-D结构类似于在脂质环境中通过NMR确定的结构。衍生的计算模型也被用于揭示几个非肽配体的结合模式，并合理化配体的结构-活性关系从实验中已知。我们的研究结果确实支持我们的“验证CCK 1 R模型”可以用于研究CCK 1 R激活的内在机制和设计新的配体。
The Cholecystokinin-1 receptor (CCK1R) mediates actions of CCK in areas of the central nervous system and of the gut. It is a potential target to treat a number of diseases. As for all G-protein-coupled receptors, docking of ligands into modeled CCK1R binding site should greatly help to understand intrinsic mechanisms of activation. Here, we describe the procedure we used to progressively build a structural model for the CCK1R, to integrated, and on the basis of site-directed mutagenesis data on its binding site. Reliability of the CCK1R model was confirmed by interaction networks that involved conserved and functionally crucial motifs in G-protein-coupled receptors, such as Glu/Asp-Arg-Tyr and Asn-Pro-Xaa-Xaa-Tyr motifs. In addition, the 3-D structure of CCK1R-bound CCK resembled that determined by NMR in a lipid environment. The derived computational model was also used for revealing binding modes of several nonpeptide ligands and for rationalizing ligand structure-activity relationships known from experiments. Our findings indeed support that our "validated CCK1R model" could be used to study the intrinsic mechanism of CCK1R activation and design new ligands.