Structure-based design of nonnatural ligands for the HLA-B27 protein

作     者：Dédier, S Krebs, S Lamas, JR Poenaru, S Folkers, G de Castro, JAL Seebach, D Rognan, D 

作者机构：Swiss Fed Inst Technol Dept Pharm CH-8057 Zurich Switzerland Swiss Fed Inst Technol Organ Chem Lab CH-8092 Zurich Switzerland Univ Autonoma Madrid Ctr Biol Mol Severo Ochoa Fac Ciencias E-28049 Madrid Spain 

出 版 物：《JOURNAL OF RECEPTOR AND SIGNAL TRANSDUCTION RESEARCH》 (受体与信号转导杂志)

年 卷 期：1999年第19卷第1-4期

页      面：645-657页

核心收录：

学科分类：0710[理学-生物学] 07[理学] 09[农学] 

主　　题：亲和力标记物/化学合成 亲和力标记物/化学 亲和力标记物/代谢 氨基酸序列 圆二色性 药物设计 HLA-B27抗原/化学 HLA-B27抗原/代谢 配体 寡肽类/化学合成 寡肽类/化学 寡肽类/代谢 蛋白质变性 重组融合蛋白质类/化学 重组融合蛋白质类/代谢 构效关系 人类 

摘      要：X-ray studies as well as structure-activity relationships indicate that the central part of class I MHC-binding nonapeptides represents the main interaction site for a T cell receptor. In order to rationally manipulate T cell epitopes, several nonpeptidic spacer have been designed from the X-ray structure of a MHC-peptide complex and substituted for the T cell receptor-binding part of several antigenic peptides. The binding of the modified epitopes to the HLA-B*2705 protein was studied by an in vitro stabilisation assay and the thermal stability of all complexes examined by circular dichroism spectroscopy. Depending on their chemical nature and length, the introduced spacers may be classified into two categories. Monofunctional spacers (11-amino undecanoate, (R)-3-hydroxybutyrate trimer) simply link two anchoring peptide positions (P3 and P9) but loosely contact the MHC binding groove, acid thus decrease more or less the affinity of the altered epitopes to HLA-B*2705. Bifunctional spacers ((R)-3-hydroxybutyrate and beta-homoalanine combinations) not only bridges the two distant anchoring amino acids but also strongly interact with the binding cleft and lead to an increase in binding to the MHC protein. The presented modified ligands constitute interesting tools for perturbing the T cell response to the parent antigenic peptide.