Grommé M, van der Valk R, Sliedregt K, Vernie L, Liskamp R, Hämmerling G, Koopmann J O, Momburg F, Neefjes J
Division of Cellular Biochemistry, Netherlands Cancer Institute, Amsterdam.
Eur J Immunol. 1997 Apr;27(4):898-904. doi: 10.1002/eji.1830270415.
The major histocompatibility complex (MHC)-encoded transporter associated with antigen processing (TAP) translocates peptides from the cytosol into the lumen of the endoplasmic reticulum. This step precedes the binding of peptides to MHC class I molecules and is essential for cell surface expression of the MHC class I/peptide complex. TAP has a broad sequence specificity and a preference for peptides of around 9 amino acids. To synthesize inhibitors for TAP, we studied various alterations of the peptide substrate. The results indicate that TAP is stereospecific and that peptide bonds engineered into isosteric structures can improve translocation of the peptide. Furthermore, TAP is able to translocate peptides with large side chains that correspond to a peptide of approximately 21 amino acids in extended conformation. Peptides with longer side chains compete for the peptide binding site of TAP but fail to be translocated. Therefore, they represent the first rationally designed inhibitors of TAP.
主要组织相容性复合体（MHC）编码的与抗原加工相关的转运体（TAP）将肽从细胞质转运到内质网腔中。这一步骤先于肽与MHC I类分子的结合，并且对于MHC I类/肽复合物在细胞表面的表达至关重要。TAP具有广泛的序列特异性，并且偏好约9个氨基酸的肽。为了合成TAP的抑制剂，我们研究了肽底物的各种改变。结果表明TAP具有立体特异性，并且工程改造为等排结构的肽键可以改善肽的转运。此外，TAP能够转运具有大侧链的肽，这些侧链对应于伸展构象下约21个氨基酸的肽。具有更长侧链的肽竞争TAP的肽结合位点，但不能被转运。因此，它们代表了首批合理设计的TAP抑制剂。
