3CCH

H-2Db complex with murine gp100

Summary for 3CCH

• Entry DOI: 10.2210/pdb3cch/pdb
• Related: 3CH1
• Descriptor: H-2 class I histocompatibility antigen, D-B alpha chain, Beta-2-microglobulin, nonameric peptide murine gp100, ... (6 entities in total)
• Functional Keywords: murine mhc, glycoprotein, immune response, membrane, mhc i, transmembrane, disease mutation, melanin biosynthesis, immune system
• Biological source: Mus musculus (mouse); More
• Cellular location: Membrane; Single-pass type I membrane protein: P01899; Secreted: P01887
• Total number of polymer chains: 12
• Total formula weight: 181974.50

Authors

Badia-Martinez, D.,Achour, A. (deposition date: 2008-02-25, release date: 2009-03-10, Last modification date: 2024-10-16)

Primary citation

van Stipdonk, M.J.,Badia-Martinez, D.,Sluijter, M.,Offringa, R.,van Hall, T.,Achour, A.
Design of agonistic altered peptides for the robust induction of CTL directed towards H-2Db in complex with the melanoma-associated epitope gp100.
Cancer Res., 69:7784-7792, 2009

PubMed Abstract: Immunogenicity of tumor-associated antigens (TAA) is often weak because many TAA are autoantigens for which the T-cell repertoire is sculpted by tolerance mechanisms. Substitutions at main anchor positions to increase the complementarity between the peptide and the MHC class I (MHC-I) binding cleft constitute a common procedure to improve binding capacity and immunogenicity of TAA. However, such alterations are tailored for each MHC-I allele and may recruit different CTL specificities through conformational changes in the targeted peptides. Comparative analysis of substituted melanoma-differentiation antigen gp100 in complex with H-2D(b) revealed that combined introduction of glycine and proline residues at the nonanchor positions 2 and 3, respectively, resulted in an agonistic altered peptide with dramatically enhanced binding affinity, stability, and immunogenicity of this TAA. Peptide vaccination using the p2Gp3P-altered peptide version of gp100 induced high frequencies of melanoma-specific CTL in the endogenous CD8+ repertoire. Crystal structure analysis of MHC/peptide complexes revealed that the conformation of the modified p2Gp3P-peptide was similar to the wild-type peptide, and indicated that this mimotope was stabilized through interactions between peptide residue p3P and the tyrosine residue Y159 that is conserved among most known MHC-I molecules throughout mammalian species. Our results may provide an alternative approach to enhance MHC stabilization capacity and immunogenicity of low-affinity peptides for induction of robust tumor-specific CTL.

PubMed: 19789338
DOI: 10.1158/0008-5472.CAN-09-1724

Experimental method

X-RAY DIFFRACTION (2.6 Å)