Conformational restriction of the Tyr(53) side-chain in the decapeptide HEL[52-61]: effects on binding to MHC-II I-A(k) molecule and TCR recognition

A series of conformationally restricted analogs of the hen egg lysozyme (HE L) decapeptide 52-61 in which the conformationally flexible Tyr(53) residue was replaced by several more constrained tyrosine and phenylalanine analog s was prepared. Among these tyrosine and phenylalanine analogs were 1,2,3,4 -tetrahydro-7-hydroxyisoquinoline-3-carboxylic acid (Htc), 1,2,3,4-tetrahyd roisoquinoline-3-carboxy acid (Tic), 4-amino-1,2.4,5-tetrahydro-8-hydroxy-2 -benzazepine-3-one (Hba), 4-amino-1,2.4,5-tetrahydro-2-benzazepine-3-one (A ba), 2-amino-6-hydroxytetralin-2-carboxylic acid (Hat) and 2-amino-5-hydrox yindan-2-carboxylic acid (Hai) in which the rotations around C-alpha-C-beta and C-beta-C-gamma were restricted because of cyclization of the side-chai n to the backbone. Synthesis of Pht-Hba-Gly-OH using a modification of the Flynn and de Laszlo procedure is described. Analogs of B-methyltyrosine (be ta -MeTyr) in which the side-chains were biased to particular side-chain to rsional angles because of substitution at the P-hydrogens were also prepare d. These analogs of HEL[52-61] peptide were tested for their ability to bin d to the major histocompatibility complex class II I-A(k) molecule and to b e recognized in this context by two T-cell hybridomas, specific for the par ent peptide HEL[52-61]. The data showed that the conformation and also the configuration of the Tyr(53) residue influenced both the binding of the pep tide to I-Ak and the recognition of the peptide/I-A(k) complex by a T-cell receptor.