Hibert M, Hoflack J, Trumpp-Kallmeyer S, Mouillac B, Chini B, Mahé E, Cotte N, Jard S, Manning M, Barberis C
Marion Merrell Dow, Strasbourg, France.
J Recept Signal Transduct Res. 1999 Jan-Jul;19(1-4):589-96. doi: 10.3109/10799899909036674.
Three-dimensional models of G protein-coupled receptors (GPCR) have been defined using most experimental data available and protein modeling techniques. The endogenous ligand binding sites have been qualitatively described and putative receptor activation mechanisms have been proposed. The model has been recently refined to take into account recent crystallographic data. Most experimental results published are in excellent qualitative agreement with the initial model. We have undertaken to study more systematically by site directed mutagenesis the vasopressin/oxytocin receptor binding domain as a prototype of neuropeptide receptors. The experimental results are in very good agreement with the models. The residues responsible for the neuropeptide binding have been identified and confirm the predicted localization of the neuromediator in the transmembrane domain of the receptors. The side chain of the 8th residue of vasopressin interacts with a non-conserved receptor residue located in the first extracellular loop. As predicted from the model, this interaction is completely responsible for the selectivity of the ligand-receptor interaction. Finally, aromatic residues which allow the modulation of the efficacy of agonists have been identified.
利用现有的大多数实验数据和蛋白质建模技术，已确定了G蛋白偶联受体（GPCR）的三维模型。对内源性配体结合位点进行了定性描述，并提出了假定的受体激活机制。最近对该模型进行了完善，以纳入最新的晶体学数据。已发表的大多数实验结果与初始模型在质量上高度一致。我们已着手通过定点诱变更系统地研究血管加压素/催产素受体结合域，将其作为神经肽受体的一个原型。实验结果与模型非常吻合。已确定了负责神经肽结合的残基，并证实了神经介质在受体跨膜域中的预测定位。血管加压素第8位残基的侧链与位于第一个细胞外环中的一个非保守受体残基相互作用。正如从模型中预测的那样，这种相互作用完全决定了配体-受体相互作用的选择性。最后，已确定了能够调节激动剂效力的芳香族残基。
