Kersh G J, Miley M J, Nelson C A, Grakoui A, Horvath S, Donermeyer D L, Kappler J, Allen P M, Fremont D H
Department of Pathology and Center for Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
J Immunol. 2001 Mar 1;166(5):3345-54. doi: 10.4049/jimmunol.166.5.3345.
To better understand TCR discrimination of multiple ligands, we have analyzed the crystal structures of two Hb peptide/I-E(k) complexes that differ by only a single amino acid substitution at the P6 anchor position within the peptide (E73D). Detailed comparison of multiple independently determined structures at 1.9 A resolution reveals that removal of a single buried methylene group can alter a critical portion of the TCR recognition surface. Significant variance was observed in the peptide P5-P8 main chain as well as a rotamer difference at LeuP8, approximately 10 A distal from the substitution. No significant variations were observed in the conformation of the two MHC class II molecules. The ligand alteration results in two peptide/MHC complexes that generate bulk T cell responses that are distinct and essentially nonoverlapping. For the Hb-specific T cell 3.L2, substitution reduces the potency of the ligand 1000-fold. Soluble 3.L2 TCR binds the two peptide/MHC complexes with similar affinity, although with faster kinetics. These results highlight the role of subtle variations in MHC Ag presentation on T cell activation and signaling.
为了更好地理解TCR对多种配体的识别，我们分析了两种Hb肽/I-E(k)复合物的晶体结构，这两种复合物在肽段的P6锚定位置（E73D）仅存在一个氨基酸替换。对多个独立测定的分辨率为1.9 Å的结构进行详细比较后发现，去除一个单个的埋藏亚甲基可改变TCR识别表面的关键部分。在肽段的P5 - P8主链以及距替换位点约10 Å处的LeuP8处的旋转异构体差异中观察到显著变化。在两个II类MHC分子的构象中未观察到显著变化。配体的改变导致两种肽/MHC复合物产生截然不同且基本不重叠的大量T细胞反应。对于Hb特异性T细胞3.L2，替换使配体的效力降低了1000倍。可溶性3.L2 TCR以相似的亲和力结合这两种肽/MHC复合物，尽管动力学更快。这些结果突出了MHC抗原呈递中的细微变化在T细胞活化和信号传导中的作用。
