Chini B, Mouillac B, Ala Y, Balestre M N, Cotte N, Trumpp-Kallmeyer S, Hoflack J, Elands J, Hibert M, Manning M
Unité INSERM 401, CCIPE, Montpellier, France.
Adv Exp Med Biol. 1995;395:321-8.
Vasopressin (AVP) and oxytocin (OT) are two nonapeptides differing at position 3, in the cyclic part of the peptide, and at position 8, in the C-terminal tripeptide. In this study, we have evaluated the interactions between these two positions of the hormones and the oxytocin receptor (OTR), the V1a and the V2 vasopressin receptors. The contribution of these two positions to receptor selectivity was analyzed by using several peptide analogues bearing substitutions at either position 3 or 8. The putative interactions between receptor residues and hormone residues at position 3 and 8 were then deduced by using a three dimensional model of the neurohypophysial hormones docked into their respective receptors. On the basis of this model, we found that the lateral chain of residue 8 might interact with residues located in the first extracellular loop. By using site-directed mutagenesis on the cloned receptors, we identified a non-conserved residue in the first extracellular loop that interacts with the lateral chain of residue 8 in the hormone. We demonstrated that this interaction is crucial for receptor selectivity to the different agonists.
血管加压素（AVP）和催产素（OT）是两种九肽，在肽的环状部分的第3位以及C端三肽的第8位存在差异。在本研究中，我们评估了激素这两个位置与催产素受体（OTR）、V1a和V2血管加压素受体之间的相互作用。通过使用在第3位或第8位带有取代基的几种肽类似物，分析了这两个位置对受体选择性的贡献。然后，通过将神经垂体激素对接至各自受体的三维模型，推断受体残基与第3位和第8位激素残基之间的假定相互作用。基于该模型，我们发现第8位残基的侧链可能与位于第一个细胞外环中的残基相互作用。通过对克隆受体进行定点诱变，我们在第一个细胞外环中鉴定出一个与激素中第8位残基的侧链相互作用的非保守残基。我们证明这种相互作用对于受体对不同激动剂的选择性至关重要。
