Weiss G A, Collins E J, Garboczi D N, Wiley D C, Schreiber S L
Department of Chemistry, Harvard University, Cambridge, MA 02138, USA.
Chem Biol. 1995 Jun;2(6):401-7. doi: 10.1016/1074-5521(95)90221-x.
Cytotoxic T-lymphocytes (CTLs) recognize complexes of short peptides with major histocompatibility complex (MHC) class I molecules. MHC molecules are polymorphic, and the products of different MHC alleles bind to different subsets of peptides. This is due to differences in the shape of the peptide-binding groove on the surface of the MHC protein, especially the 'pockets' into which anchor residues at each end of the peptide fit. Non-peptidic ligands for class I molecules may be useful clinically.
By applying computer-aided design methods guided by X-ray structures, we designed and synthesized several MHC class I ligands, based on known peptide ligands, in which the tricyclic, aromatic compound phenanthridine replaced the central amino acids of the peptides. These semi-peptidic fluorescent ligands bound with high affinity and with allelic specificity to the peptide-binding groove of different MHC class I molecules, forming crystallizable complexes.
Specificity for binding to different MHC class I molecules can be imparted to the common phenanthridine element by judicious choice of terminal peptidic elements from either nonamer or decamer peptides. The phenanthridine-based ligands have a long bound half-life, as do antigenic peptides.
细胞毒性T淋巴细胞（CTLs）识别短肽与主要组织相容性复合体（MHC）I类分子形成的复合物。MHC分子具有多态性，不同MHC等位基因的产物结合不同的肽亚群。这是由于MHC蛋白表面肽结合槽形状的差异，特别是肽两端的锚定残基所契合的“口袋”。I类分子的非肽配体在临床上可能有用。
通过应用以X射线结构为指导的计算机辅助设计方法，我们基于已知的肽配体设计并合成了几种MHC I类配体，其中三环芳香化合物菲啶取代了肽的中心氨基酸。这些半肽荧光配体以高亲和力和等位基因特异性结合到不同MHC I类分子的肽结合槽，形成可结晶的复合物。
通过明智地选择九聚体或十聚体肽的末端肽元件，可以赋予常见的菲啶元件与不同MHC I类分子结合的特异性。基于菲啶的配体具有与抗原肽一样长的结合半衰期。
