4IS6

Crystal structure of HLA-DR4 bound to GP100 peptide

4IS6 の概要

• エントリーDOI: 10.2210/pdb4is6/pdb
• 分子名称: HLA class II histocompatibility antigen, DR alpha chain, HLA class II histocompatibility antigen, DRB1-4 beta chain, Melanocyte protein PMEL, ... (4 entities in total)
• 機能のキーワード: mhc class ii, hla-dr4, gp100, immune system
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Cell membrane; Single-pass type I membrane protein: P01903 P13760; Endoplasmic reticulum membrane; Single-pass type I membrane protein. M-alpha: Secreted: P40967
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 45783.21

構造登録者

Li, Y. (登録日: 2013-01-16, 公開日: 2013-10-23, 最終更新日: 2024-11-27)

主引用文献

Chen, S.,Li, Y.,Depontieu, F.R.,McMiller, T.L.,English, A.M.,Shabanowitz, J.,Kos, F.,Sidney, J.,Sette, A.,Rosenberg, S.A.,Hunt, D.F.,Mariuzza, R.A.,Topalian, S.L.
Structure-Based Design of Altered MHC Class II-Restricted Peptide Ligands with Heterogeneous Immunogenicity.
J.Immunol., 191:5097-5106, 2013

PubMed Abstract: Insights gained from characterizing MHC-peptide-TCR interactions have held the promise that directed structural modifications can have predictable functional consequences. The ability to manipulate T cell reactivity synthetically or through genetic engineering might thus be translated into new therapies for common diseases such as cancer and autoimmune disorders. In the current study, we determined the crystal structure of HLA-DR4 in complex with the nonmutated dominant gp100 epitope gp10044-59, associated with many melanomas. Altered peptide ligands (APLs) were designed to enhance MHC binding and hence T cell recognition of gp100 in HLA-DR4(+) melanoma patients. Increased MHC binding of several APLs was observed, validating this approach biochemically. Nevertheless, heterogeneous preferences of CD4(+) T cells from several HLA-DR4(+) melanoma patients for different gp100 APLs suggested highly variable TCR usage, even among six patients who had been vaccinated against the wild-type gp100 peptide. This heterogeneity prevented the selection of an APL candidate for developing an improved generic gp100 vaccine in melanoma. Our results are consistent with the idea that even conservative changes in MHC anchor residues may result in subtle, yet crucial, effects on peptide contacts with the TCR or on peptide dynamics, such that alterations intended to enhance immunogenicity may be unpredictable or counterproductive. They also underscore a critical knowledge gap that needs to be filled before structural and in vitro observations can be used reliably to devise new immunotherapies for cancer and other disorders.

PubMed: 24108701
DOI: 10.4049/jimmunol.1300467

実験手法

X-RAY DIFFRACTION (2.5 Å)