2BNQ

Structural and kinetic basis for heightened immunogenicity of T cell vaccines

Summary for 2BNQ

• Entry DOI: 10.2210/pdb2bnq/pdb
• Related: 1A1M 1A1N 1A1O 1A6Z 1A9B 1A9E 1AGB 1AGC 1AGD 1AGE 1AGF 1AKJ 1AO7 1B0G 1B0R 1BD2 1CE6 1DE4 1DUY 1DUZ 1E27 1E28 1EFX 1EXU 1FYT 1GZP 1GZQ 1HHG 1HHH 1HHI 1HHJ 1HHK 1HLA 1HSA 1HSB 1I1F 1I1Y 1I4F 1I7R 1I7T 1I7U 1IM3 1IM9 1JF1 1JGE 1JHT 1JNJ 1K5N 1KGC 1KPR 1KTL 1LDS 1OF2 1QLF 1QQD 1QR1 1QRN 1QSE 1QSF 1TMC 2BNR 2CLR 2HLA 3HLA
• Descriptor: HLA CLASS I HISTOCOMPATIBILITY ANTIGEN, BETA-2-MICROGLOBULIN, SYNTHETIC PEPTIDE, ... (6 entities in total)
• Functional Keywords: immune system/receptor, immune system-receptor-complex, tcr, mhc, immunodominance, flu, complex, transmembrane, glycoprotein, polymorphism, t-cell, receptor, superagonist peptide t-cell vaccines, immune system-receptor complex
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Membrane; Single-pass type I membrane protein: P01892; Secreted : P61769; Membrane ; Single-pass membrane protein : 2BNQ
• Total number of polymer chains: 5
• Total formula weight: 94098.47

Authors

Chen, J.-L.,Stewart-Jones, G.,Bossi, G.,Lissin, N.M.,Wooldridge, L.,Choi, E.M.L.,Held, G.,Dunbar, P.R.,Esnouf, R.M.,Sami, M.,Boultier, J.M.,Rizkallah, P.J.,Renner, C.,Sewell, A.,van der Merwe, P.A.,Jackobsen, B.K.,Griffiths, G.,Jones, E.Y.,Cerundolo, V. (deposition date: 2005-03-31, release date: 2005-05-23, Last modification date: 2023-12-13)

Primary citation

Chen, J.-L.,Stewart-Jones, G.,Bossi, G.,Lissin, N.M.,Wooldridge, L.,Choi, E.M.L.,Held, G.,Dunbar, P.R.,Esnouf, R.M.,Sami, M.,Boultier, J.M.,Rizkallah, P.,Renner, C.,Sewell, A.,Van Der Merwe, P.A.,Jackobsen, B.K.,Griffiths, G.,Jones, E.Y.,Cerundolo, V.
Structural and Kinetic Basis for Heightened Immunogenicity of T Cell Vaccines
J.Exp.Med., 201:1243-, 2005

PubMed Abstract: Analogue peptides with enhanced binding affinity to major histocompatibility class (MHC) I molecules are currently being used in cancer patients to elicit stronger T cell responses. However, it remains unclear as to how alterations of anchor residues may affect T cell receptor (TCR) recognition. We correlate functional, thermodynamic, and structural parameters of TCR-peptide-MHC binding and demonstrate the effect of anchor residue modifications of the human histocompatibility leukocyte antigens (HLA)-A2 tumor epitope NY-ESO-1(157-165)-SLLMWITQC on TCR recognition. The crystal structure of the wild-type peptide complexed with a specific TCR shows that TCR binding centers on two prominent, sequential, peptide sidechains, methionine-tryptophan. Cysteine-to-valine substitution at peptide position 9, while optimizing peptide binding to the MHC, repositions the peptide main chain and generates subtly enhanced interactions between the analogue peptide and the TCR. Binding analyses confirm tighter binding of the analogue peptide to HLA-A2 and improved soluble TCR binding. Recognition of analogue peptide stimulates faster polarization of lytic granules to the immunological synapse, reduces dependence on CD8 binding, and induces greater numbers of cross-reactive cytotoxic T lymphocyte to SLLMWITQC. These results provide important insights into heightened immunogenicity of analogue peptides and highlight the importance of incorporating structural data into the process of rational optimization of superagonist peptides for clinical trials.

PubMed: 15837811
DOI: 10.1084/JEM.20042323

Experimental method

X-RAY DIFFRACTION (1.7 Å)