       Document 0243
 DOCN  M9610243
 TI    Relative implication of peptide residues in binding to major
       histocompatibility complex class I H-2Db: application to the design of
       high-affinity, allele-specific peptides.
 DT    9601
 AU    Hudrisier D; Mazarguil H; Oldstone MB; Gairin JE; Laboratoire de
       Pharmacologie et Toxicologie Fondamentales, CNRS,; Toulouse, France.
 SO    Mol Immunol. 1995 Aug;32(12):895-907. Unique Identifier : AIDSLINE
       MED/96032869
 AB    The H-2Db peptide sequence SMIENLEYM was manipulated (N- and C-terminus
       truncation and alanine substitution) to determine the role of structural
       elements (peptide ends and residue side chains) in binding to H-2Db. We
       found that good binding affinity could be obtained by compensating the
       minimal binding condition for one element by the optimal condition of
       the other element. In particular, we showed, that although the minimal
       binding sequence could be as short as a heptamer (deletion of positions
       1 and 2), it needed the presence of optimal amino acids at other
       positions (IENLEYM). Conversely, the structurally minimal peptide would
       accept multiple alanine residues, but required the optimal nonameric
       length (AAAENAEAA). Positions 1, 2, 3, 4, 5, 7 and 9, but not 6 and 8,
       were involved in the H-2Db-peptide interaction. Most residues interacted
       directly with the MHC molecule via their main chain (amino and carboxyl)
       atoms (positions 1 and 2), their side chains (positions 3 and 5), or
       both (position 9). Positions 4 and 7 were found to play an indirect
       role, probably by influencing the secondary structure. At the
       C-terminus, the presence of a residue at position 9, but not the
       hydrophobic nature of its side chain, was mandatory for binding. At the
       N-terminus, the role of the residue at position 1 was of either minor or
       critical importance depending on the presence or not of a strong
       auxiliary anchor at position 3. The indirect contribution of residue
       side chains at positions 4 and 7 reflected the importance of dynamic
       components in the binding process. Based on these results, we designed a
       series of high-affinity, H-2Db selective peptides derived from the
       sequence X1 AIX4NAEAL, where X1 = Y or K and X4 = E or K. After
       radioiodination or fluorescent (FITC) labelling, these peptides bound
       strongly and specifically to the surface of viable H-2Db-expressing
       cells. Rationally designed synthetic peptides, either alone or in a
       stable complex with MHC, might be of value for controlling CTL activity.
 DE    Alleles  Amino Acid Sequence  Animal  Binding Sites  Cell Line
       CD8-Positive T-Lymphocytes/IMMUNOLOGY  Drug Design  H-2
       Antigens/*METABOLISM  Mice  Molecular Sequence Data
       Oligopeptides/GENETICS/IMMUNOLOGY/*METABOLISM  Protein Binding  Protein
       Engineering  Support, Non-U.S. Gov't  Support, U.S. Gov't, P.H.S.
       JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

