6tgg
From Proteopedia
scFv-1SM3 in complex with glycopeptide containing an sp2-imino sugar
Structural highlights
Disease[MUC1_HUMAN] Note=MUC1/CA 15-3 is used as a serological clinical marker of breast cancer to monitor response to breast cancer treatment and disease recurrence (PubMed:20816948). Decreased levels over time may be indicative of a positive response to treatment. Conversely, increased levels may indicate disease progression. At an early stage disease, only 21% of patients exhibit high MUC1/CA 15-3 levels, that is why CA 15-3 is not a useful screening test. Most antibodies target the highly immunodominant core peptide domain of 20 amino acid (APDTRPAPGSTAPPAHGVTS) tandem repeats. Some antibodies recognize glycosylated epitopes. Function[MUC1_HUMAN] The alpha subunit has cell adhesive properties. Can act both as an adhesion and an anti-adhesion protein. May provide a protective layer on epithelial cells against bacterial and enzyme attack.[1] [2] [3] [4] [5] [6] [7] [8] [9] The beta subunit contains a C-terminal domain which is involved in cell signaling, through phosphorylations and protein-protein interactions. Modulates signaling in ERK, SRC and NF-kappa-B pathways. In activated T-cells, influences directly or indirectly the Ras/MAPK pathway. Promotes tumor progression. Regulates TP53-mediated transcription and determines cell fate in the genotoxic stress response. Binds, together with KLF4, the PE21 promoter element of TP53 and represses TP53 activity.[10] [11] [12] [13] [14] [15] [16] [17] [18] Publication Abstract from PubMedThe Tn antigen (GalNAc-alpha-1-O-Thr/Ser) is a well-known tumor-associated carbohydrate determinant. The use of glycopeptides that incorporate this structure has become a significant and promising niche of research owing to their potential use as anticancer vaccines. Herein, the conformational preferences of a glycopeptide with an unnatural Tn antigen, characterized by a threonine decorated with an sp(2)-iminosugar-type alpha-GalNAc mimic, have been studied both in solution, by combining NMR spectroscopy and molecular dynamics simulations, and in the solid state bound to an anti-mucin-1 (MUC1) antibody, by X-ray crystallography. The Tn surrogate can mimic the main conformer sampled by the natural antigen in solution and exhibits high affinity towards anti-MUC1 antibodies. Encouraged by these data, a cancer vaccine candidate based on this unnatural glycopeptide and conjugated to the carrier protein Keyhole Limpet Hemocyanin (KLH) has been prepared and tested in mice. Significantly, the experiments in vivo have proved that this vaccine elicits higher levels of specific anti-MUC1 IgG antibodies than the analog that bears the natural Tn antigen and that the elicited antibodies recognize human breast cancer cells with high selectivity. Altogether, we compile evidence to confirm that the presentation of the antigen, both in solution and in the bound state, plays a critical role in the efficacy of the designed cancer vaccines. Moreover, the outcomes derived from this vaccine prove that there is room for exploring further adjustments at the carbohydrate level that could contribute to designing more efficient cancer vaccines. Synthesis, conformational analysis and in vivo assays of an anti-cancer vaccine that features an unnatural antigen based on an sp(2)-iminosugar fragment.,Bermejo IA, Navo CD, Castro-Lopez J, Guerreiro A, Jimenez-Moreno E, Sanchez Fernandez EM, Garcia-Martin F, Hinou H, Nishimura SI, Garcia Fernandez JM, Mellet CO, Avenoza A, Busto JH, Bernardes GJL, Hurtado-Guerrero R, Peregrina JM, Corzana F Chem Sci. 2020 Mar 27;11(15):3996-4006. doi: 10.1039/c9sc06334j. PMID:34122869[19] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Large Structures | Lk3 transgenic mice | Avenoza, A | Bermejo, I A | Bernardes, G J.L | Busto, J H | Castro-Lopez, J | Corzana, F | Garcia-Fernandez, J M | Garcia-Martin, F | Guerreiro, A | Hurtado-Guerrero, R | Navo, C D | Nishimura, S I | Ortiz-Mellet, C | Peregrina, J M | Samchez-Fernandez, E M | Anti cancer vaccine | Antibody | Antigen tn | Antitumor protein | Conformational analysis | Iminosugar | Scfv
