RECEPTOR BINDING DOMAIN OF PEPTIDE AGONISTS

在绘制受体结合图谱方面已经取得了相当大的进展 然而，阳离子生物胺激素的研究进展甚微， 确定G蛋白结合位点的性质 偶联受体结合肽配体的大小范围从三个 （fMLP）至数百个残基（LH和FSH）。 很明显，所有G- 蛋白偶联受体具有一些共同的结构特征，然而， 在结合结构域方面也有很大的不同。 在 这个建议，我们选择阐明的结合域的 白细胞介素-8受体属于G蛋白超家族 偶联受体 白细胞介素-8（IL-8）是由72个氨基酸组成的多肽 由许多类型的细胞响应促炎刺激而分泌， 白细胞介素-1和肿瘤坏死因子。 IL-8诱导跨内皮细胞 具有新的白细胞介素-8受体亚型的迁移克隆 关于结构相关肽的配体结合特异性， 中性粒细胞活化肽2与黑色素瘤生长刺激 活动（MGSA）。 我们确定配体结合特异性是 由细胞外N-末端决定，以鉴定 IL-8/受体接口通过使用遗传方法。 绘制氨基酸图谱 配体-受体界面的酸残基将有助于设计 新的IL-8受体拮抗剂，将影响治疗 炎症性疾病

Considerable progress has been achieved on mapping the receptor binding site of cationic biogenic amine hormones, however, little progress has been made on determining the nature of the binding site of G-protein coupled receptors that bind peptide ligands of sizes that range from three (fMLP) to several hundred residues (LH and FSH). It is clear that all G- protein coupled receptors share some common structural features, however, there are also major differences with regard to the binding domain. In this proposal we choose to elucidate the binding domain of the interleukin-8 receptor which belongs to the superfamily of G-protein coupled receptors. Interleukin-8 (IL-8) is a 72 amino acid peptide secreted by many cell types in response to proinflammatory stimuli such as interleukin-1, and tumor necrosis factor. IL-8 induces transendothelial migration cloning of Interleukin-8 receptor subtypes exhibiting novel ligand binding specificity with regard to structurally related peptides, neutrophil activating peptide 2 (NAP-2) and melanoma growth stimulating activity (MGSA). We determined that the ligand binding specificity is dictated by the extracellular N-terminus to identify the residues at the IL-8/receptor interface by using a genetic approach. Mapping the amino acid residues at the ligand-receptor interface will aid toward the design of novel IL-8 receptor antagonists that will impact in the treatment of inflammatory disorders.