Identifizierung der Rezeptorinteraktion von RF-amid-Peptiden auf molekularer Ebene

人的RF-酰胺-肽由8-26个氨基酸组成，C末端含有一个特征的Arg-Phe-酰胺-二肽基序。目前已有6种RF-酰胺类多肽在人体内被发现。在过去的两年里，这个多肽家族受到了极大的关注，主要是因为它具有重要的药理活性，如调节疼痛、控制压力、调节昼夜节律和食物摄入量。这些多肽与人体内属于G蛋白偶联受体家族的4种受体结合。我们最近已经确定了神经肽Y的配体结合部位，并基于这些数据，我们假设了RF-酰胺肽的保守Arg残基与相应受体的Asp6.59残基之间存在着强烈的离子和重要的相互作用。我们计划利用合成肽类似物、受体突变和互补相互作用研究在分子水平上鉴定配体结合口袋。这可能有助于全面了解与GPCRs相互作用的多肽的结合和信号转导。此外，我们的数据可以支持这些体系中的药物开发，并阐明RF-酰胺多肽的配体选择性这一重要问题。由于RF-酰胺多肽家族的进化，我们可能有助于更好地理解配体和受体的共同进化。

RF-amide-peptides consist of 8-26 amino acids in human and contain C-terminally a characteristic Arg-Phe-amide-dipeptide motif. Six RF-amide-peptides have been described in human. For the last two years this peptide family has gained significant interest mainly because of its pharmacologically important activities like modulation of pain, stress control, regulation of day/night rhythm and food intake. The peptides bind to 4 receptors in human that all belong to the family of G-protein coupled receptors. We recently could identify the ligand binding site of neuropeptide Y and based on these data we hypothesize a strong ionic and important interaction of the conserved Arg residue of the RF-amide peptides with residue Asp6.59 of the correspondent receptor. We plan to use synthetic peptide analogues, receptor mutagenesis and complementary interaction studies to identify the ligand binding pocket on a molecular level. This might contribute significantly to the overall understanding of binding and signal transduction of peptides that interact with GPCRs. Furthermore, our data could support drug development in these systems and clarify the important problem of ligand selectivity of RF-amide peptides. Owing to the evolutionary old family of RF-amide peptides we might contribute to a better understanding of the coevolution of ligands and receptors.