Small organic compounds enhance antigen loading of class II major histocompatibility complex proteins by targeting the polymorphic P1 pocket
Small organic compounds enhance antigen loading of class II major histocompatibility complex proteins by targeting the polymorphic P1 pocket
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DOI：
10.1074/jbc.m606437200
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发表时间：
2006-12-15
影响因子：
4.8
通讯作者：
Roetzschke, Olaf
中科院分区：
文献类型：
--
作者：
Hoepner, Sabine;Dickhaut, Katharina;Roetzschke, Olaf
主要组织相容性复合体（MHC）分子是细胞免疫应答的关键要素。由MHC编码，它们是高度多态性肽受体家族，呈递肽抗原以供T细胞监视。我们已经表明，某些有机化合物可以通过催化人类II类MHC分子HLA-DR的肽加载来放大免疫反应。在这里，我们现在表明，它们通过与HLA-DR肽受体的定义结合位点相互作用来实现这一点。化合物库的筛选揭示了一组金刚烷衍生物，其强烈地加速肽加载速率。该效应仅对等位基因亚群是明显的，并且与HLA-DR分子的二态性位置β 86处的甘氨酸的存在严格相关。该残基形成保守口袋P1的底板，位于MHC分子的肽结合位点。显然，有机化合物对该口袋的瞬时占据稳定了肽接受构象，从而允许快速抗原加载。这种相互作用似乎仅限于较大的Gly（β 86）口袋，并允许显著增强T细胞对这些"金刚烷基敏感" MHC分子呈递的抗原的应答。作为抗原负载的催化剂，靶向P1的化合物可能是放大免疫应答的有用分子工具。然而，观察到的配体库可以通过多态性位点的影响，从外部也可能意味着环境因素可以诱导过敏或自身免疫反应的等位基因选择性的方式。
Major histocompatibility complex (MHC) molecules are a key element of the cellular immune response. Encoded by the MHC they are a family of highly polymorphic peptide receptors presenting peptide antigens for the surveillance by T cells. We have shown that certain organic compounds can amplify immune responses by catalyzing the peptide loading of human class II MHC molecules HLA-DR. Here we show now that they achieve this by interacting with a defined binding site of the HLA-DR peptide receptor. Screening of a compound library revealed a set of adamantane derivatives that strongly accelerated the peptide loading rate. The effect was evident only for an allelic subset and strictly correlated with the presence of glycine at the dimorphic position beta 86 of the HLA-DR molecule. The residue forms the floor of the conserved pocket P1, located in the peptide binding site of MHC molecule. Apparently, transient occupation of this pocket by the organic compound stabilizes the peptide-receptive conformation permitting rapid antigen loading. This interaction appeared restricted to the larger Gly(beta 86) pocket and allowed striking enhancements of T cell responses for antigens presented by these "adamantyl-susceptible" MHC molecules. As catalysts of antigen loading, compounds targeting P1 may be useful molecular tools to amplify the immune response. The observation, however, that the ligand repertoire can be affected through polymorphic sites form the outside may also imply that environmental factors could induce allergic or autoimmune reactions in an allele-selective manner.