The rational design of TAP inhibitors using peptide substrate modifications and peptidomimetics
| Autor: | Jacques Neefjes, K. Sliedregt, G. J. Hämmerling, Frank Momburg, Monique Grommé, L.N. Vernie, Jens-Oliver Koopmann, Rob M. J. Liskamp, R. van der Valk |
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| Rok vydání: | 1997 |
| Předmět: |
Peptidomimetic
Immunology Peptide Peptide binding Biology Binding Competitive Substrate Specificity Major Histocompatibility Complex ATP Binding Cassette Transporter Subfamily B Member 3 MHC class I Immunology and Allergy Peptide bond Amino Acid Sequence ATP Binding Cassette Transporter Subfamily B Member 2 Peptide sequence chemistry.chemical_classification Stereoisomerism Transporter associated with antigen processing ATP-Binding Cassette Sub-Family B Member 2 Biochemistry chemistry Drug Design biology.protein ATP-Binding Cassette Transporters Peptides Protein Binding |
| Zdroj: | European Journal of Immunology. 27:898-904 |
| ISSN: | 1521-4141 0014-2980 |
| DOI: | 10.1002/eji.1830270415 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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