PDBsum entry 1klg

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Immune system/toxin PDB id
Protein chains
177 a.a. *
187 a.a. *
15 a.a. *
231 a.a. *
Waters ×275
* Residue conservation analysis

References listed in PDB file
Key reference
Title Minor structural changes in a mutated human melanoma antigen correspond to dramatically enhanced stimulation of a cd4+ tumor-Infiltrating lymphocyte line.
Authors E.J.Sundberg, M.W.Sawicki, S.Southwood, P.S.Andersen, A.Sette, R.A.Mariuzza.
Ref. J Mol Biol, 2002, 319, 449-461. [DOI no: 10.1016/S0022-2836(02)00370-4]
PubMed id 12051920
While most immunotherapies for cancer have focused on eliciting specific CD8+ cytotoxic T lymphocyte killing of tumor cells, a mounting body of evidence suggests that stimulation of anti-tumor CD4+ T cell help may be required for highly effective therapy. Several MHC class II-restricted tumor antigens that specifically activate such CD4+ helper T lymphocytes have now been identified, including one from a melanoma tumor that is caused by a single base-pair mutation in the glycolytic enzyme triosephosphate isomerase. This mutation results in the conversion of a threonine residue to isoleucine within the antigenic epitope, concomitant with a greater than five log-fold increase in stimulation of a CD4+ tumor-infiltrating lymphocyte line. Here, we present the crystal structures of HLA-DR1 in complex with both wild-type and mutant TPI peptide antigens, the first structures of tumor peptide antigen/MHC class II complexes recognized by CD4+ T cells to be reported. These structures show that very minor changes in the binding surface for T cell receptor correspond to the dramatic differences in T cell stimulation. Defining the structural basis by which CD4+ T cell help is invoked in an anti-tumor immune response will likely aid the design of more effective cancer immunotherapies.
Figure 1.
Figure 1. The wild-type and mutant TPI[23-37] peptide/HLA-DR1/SEC3-3B2 complex structures. s[A]-Weighted 2F[o] -F[c] electron density maps in which the TPI[23-37] peptide atoms have been omitted from the map calculation for (a) the wild-type TPI[23-37] peptide and (b) the mutant TPI[23-37] peptide. Maps are contoured at 1.0s. (c) Superposition of the overall wild-type and mutant TPI[23-37] peptide/HLA-DR1/SEC3-3B2 complex structures. In all panels, colors are as follows: wild-type TPI[23-37] peptide, yellow; mutant TPI[23-37] peptide, green; HLA-DR1 a chain, purple; HLA-DR1 b chain, cyan; SEC3-3B2, red; nitrogen atoms, blue; oxygen atoms and water molecules, red. (a) and (b) produced using Bobscript[61] and Raster3D. [62] (c) and subsequent Figures produced using MOLSCRIPT [63] and Raster3D, [62] unless otherwise noted.
Figure 4.
Figure 4. Very similar molecular surfaces are presented to the T cell receptor by HLA-DR1 complexed with both the wild-type and mutant TPI[23-37] peptides. Molecular surface of HLA-DR1 complexed with (a) the wild-type TPI[23-37] peptide and (b) the mutant TPI[23-37] peptide. Color coding is as follows: green, carbon atoms; magenta, uncharged polar atoms; red, electronegative atoms; blue, electropositive atoms. The mutation site is outlined in black. Figure produced using GRASP.[64]
The above figures are reprinted by permission from Elsevier: J Mol Biol (2002, 319, 449-461) copyright 2002.
Secondary reference #1
Title Biochemical identification of a mutated human melanoma antigen recognized by cd4(+) t cells.
Authors R.Pieper, R.E.Christian, M.I.Gonzales, M.I.Nishimura, G.Gupta, R.E.Settlage, J.Shabanowitz, S.A.Rosenberg, D.F.Hunt, S.L.Topalian.
Ref. J Exp Med, 1999, 189, 757-766.
PubMed id 10049939
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