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首页> 外文期刊>Biochemistry >Intermolecular interactions between cholecystokinin-8 and the third extracellular loop of the cholecystokinin-2 receptor.
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Intermolecular interactions between cholecystokinin-8 and the third extracellular loop of the cholecystokinin-2 receptor.

机译：胆囊收缩素8与胆囊收缩素2受体的第三个细胞外环之间的分子间相互作用。

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摘要

The structure of the third extracellular loop of the human cholecystokinin-2 receptor, CCK2-R(352-379), and its interactions with the C-terminal octapeptide of cholecystokinin (CCK-8) have been determined by high-resolution NMR and computer simulations. In the presence of dodecylphosphocholine micelles, the structure of the receptor fragment consisted of three helices, with the first and third corresponding to residues of the extracellular ends of transmembrane helices (TM) 6 and 7, respectively. The central, extracellular helix, consisting of residues 363-368, was found to be closely associated with the membrane mimetic used during the spectroscopic studies and molecular dynamics (MD) simulations. Upon titration of CCK-8 to the receptor domain, chemical shift perturbation and intermolecular NOEs (Trp30, Met31 of CCK-8 and P371, F374 of CCK2-R) indicated the formation of a stable complex and specific ligand/receptor interactions. Using the NOE-generated intermolecular contact points, extensive MD simulations of CCK-8 bound to the CCK2 receptor were carried out. The results, with CCK-8 in close proximity to TM7, differ from previous structural studies of CCK-8 association with CCK1-R, in which the ligand formed a number of interactions with TM6. These differences may play a role in the ligand specificity displayed by the CCK1 and CCK2 receptor subtypes.
机译：已通过高分辨率NMR和计算机确定了人胆囊收缩素2受体CCK2-R（352-379）的第三胞外环的结构及其与胆囊收缩素C-端八肽的相互作用（CCK-8）模拟。在十二烷基磷酸胆碱胶束的存在下，受体片段的结构由三个螺旋组成，第一个和第三个分别对应于跨膜螺旋（TM）6和7的细胞外末端的残基。发现由残基363-368组成的中央细胞外螺旋与在光谱学研究和分子动力学（MD）模拟过程中使用的膜模拟物密切相关。在将CCK-8滴定至受体结构域后，化学位移扰动和分子间NOE（CCK-8的Trp30，Met31和CCK2-R的P371，F374）表明形成了稳定的复合物和特异性配体/受体相互作用。使用NOE生成的分子间接触点，对与CCK2受体结合的CCK-8进行了广泛的MD模拟。 CCK-8紧靠TM7的结果不同于先前CCK-8与CCK1-R缔合的结构研究，在该研究中，配体与TM6形成了许多相互作用。这些差异可能在CCK1和CCK2受体亚型显示的配体特异性中起作用。

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