Department of Chemistry, Umeå University, SE-901 87 Umeå, Sweden.
J Am Chem Soc. 2011 Sep 14;133(36):14368-78. doi: 10.1021/ja2038722. Epub 2011 Aug 19.
The structural basis for antigen presentation by class II major histocompatibility complex (MHC) proteins to CD4(+) T-cells is important for understanding and possibly treating autoimmune diseases. In the work described in this paper, (E)-alkene and ethylene amide-bond isosteres were used to investigate the effect of removing hydrogen-bonding possibilities from the CII259-270 glycopeptide, which is bound by the arthritis-associated murine A(q) class II MHC protein. The isostere-modified glycopeptides showed varying and unexpectedly large losses of A(q) binding that could be linked to the dynamics of the system. Molecular dynamics (MD) simulations revealed that the backbone of CII259-270 and the A(q) protein are able to form up to 11 hydrogen bonds, but fewer than this number are present at any one time. Most of the strong hydrogen-bond interactions were formed by the N-terminal part of the glycopeptide, i.e., in the region where the isosteric replacements were made. The structural dynamics also revealed that hydrogen bonds were strongly coupled to each other; the loss of one hydrogen-bond interaction had a profound effect on the entire hydrogen-bonding network. The A(q) binding data revealed that an ethylene isostere glycopeptide unexpectedly bound more strongly to A(q) than the corresponding (E)-alkene, which is in contrast to the trend observed for the other isosteres. Analysis of the MD trajectories revealed that the complex conformation of this ethylene isostere was structurally different and had an altered molecular interaction pattern compared to the other A(q)/glycopeptide complexes. The introduced amide-bond isosteres also affected the interactions of the glycopeptide/A(q) complexes with T-cell receptors. The dynamic variation of the patterns and strengths of the hydrogen-bond interactions in the class II MHC system is of critical importance for the class II MHC/peptide/TCR signaling system.
MHC 蛋白呈递抗原的结构基础对于理解和可能治疗自身免疫性疾病非常重要。在本文所描述的工作中，使用（E）-烯烃和亚乙基酰胺键类似物来研究从关节炎相关的鼠 A(q) 类 II MHC 蛋白结合的 CII259-270 糖肽中去除氢键可能性的影响。类似物修饰的糖肽显示出不同的和出乎意料的 A(q) 结合的大量损失，这可以与系统的动力学相关联。分子动力学（MD）模拟表明，CII259-270 的骨架和 A(q) 蛋白能够形成多达 11 个氢键，但并非所有时间都存在这种数量的氢键。大多数强氢键相互作用是由糖肽的 N 端部分形成的，即类似物取代的区域。结构动力学还表明氢键彼此强烈耦合；一个氢键相互作用的丧失对整个氢键网络有深远的影响。A(q) 结合数据表明，出乎意料的是，亚乙基类似物糖肽比相应的（E）-烯烃更强地结合 A(q)，这与观察到的其他类似物的趋势相反。对 MD 轨迹的分析表明，与其他 A(q)/糖肽复合物相比，这种亚乙基类似物的复合物构象在结构上是不同的，并且具有改变的分子相互作用模式。引入的酰胺键类似物也影响了糖肽/A(q)复合物与 T 细胞受体的相互作用。在 II 类 MHC 系统中氢键相互作用的模式和强度的动态变化对于 II 类 MHC/肽/TCR 信号转导系统至关重要。
