The covalent conjugation of a 14-carbon fatty acid (myristic acid) to the N-terminal Gly residue, termed N-myristoylation, occurs in some viral proteins to dictate their pathological function. This protein lipidation reaction, however, is monitored by host cytotoxic T lymphocytes that are capable of recognizing N-terminal lipopeptide fragments in the context of major histocompatibility complex (MHC) class I molecules. In a rhesus model of human AIDS, for example, the classical MHC class I allomorph, Mamu-B*05104, was shown to bind SIV Nef-derived 4-mer lipopeptides (myristic acid-Gly-Gly-Ala-Ile; C14nef4) and present them to the CD8⁺ T-cell line, SN45. These lipopeptides accommodated in MHC class I molecules expose much shorter peptide chains than conventional MHC class I-presented 8–10-mer peptides, and the molecular mechanisms by which αβ T-cell receptors (TCRs) recognize lipopeptides currently remain unclear. An X-ray crystallographic analysis of the SN45 TCR α and β heterodimer in a form that was co-crystallized with the C14nef4-bound Mamu-B*05104 complex indicated that the amide group of the N-myristoylated glycine residue offered a primary T-cell epitope by establishing a sole hydrogen bond between its nitrogen atom and the side chain of Glu at position 101 of CDR3β. Accordingly, the Glu to Ala mutation at this position resulted in the loss of lipopeptide recognition. On the other hand, TCRs were positioned remotely from the peptide portion of C14nef4, and strong interactions were not observed. Thus, these observations provide novel structural insights into lipopeptide recognition by TCRs, which contrast sharply with the general molecular principle of peptide recognition.

中文翻译：

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TCR、MHC I 类和脂肽的三元复合物的晶体结构。

14 碳脂肪酸（肉豆蔻酸）与 N 端 Gly 残基的共价结合，称为 N-肉豆蔻酰化，发生在一些病毒蛋白中，以决定它们的病理功能。然而，这种蛋白质脂化反应由宿主细胞毒性 T 淋巴细胞监测，这些 T 淋巴细胞能够在主要组织相容性复合体 (MHC) I 类分子的背景下识别 N 端脂肽片段。例如，在人类艾滋病的恒河猴模型中，经典的 MHC I 类同种异形体 Mamu-B*05104 显示结合 SIV Nef 衍生的 4 聚体脂肽（肉豆蔻酸-Gly-Gly-Ala-Ile；C14nef4）并将它们呈现给 CD8 ⁺T 细胞系，SN45。这些包含在 MHC I 类分子中的脂肽暴露的肽链比常规 MHC I 类呈递的 8-10 聚体肽短得多，而 αβ T 细胞受体 (TCR) 识别脂肽的分子机制目前仍不清楚。对与 C14nef4 结合的 Mamu-B*05104 复合物共结晶形式的 SN45 TCR α 和 β 异二聚体的 X 射线晶体学分析表明，N-肉豆蔻酰化甘氨酸残基的酰胺基团提供了主要的 T-通过在其氮原子和 CDR3β 的 101 位 Glu 侧链之间建立唯一的氢键来构建细胞表位。因此，该位置的 Glu 到 Ala 突变导致脂肽识别的丧失。另一方面，TCR 的位置远离 C14nef4 的肽部分，并且没有观察到强相互作用。因此，这些观察结果为 TCR 识别脂肽提供了新的结构见解，这与肽识别的一般分子原理形成鲜明对比。