3VRI

HLA-B*57:01-RVAQLENVYI in complex with abacavir

3VRI の概要

• エントリーDOI: 10.2210/pdb3vri/pdb
• 関連するPDBエントリー: 3VRJ
• 分子名称: HLA class I histocompatibility antigen, B-57 alpha chain, Beta-2-microglobulin, 10-mer peptide, ... (6 entities in total)
• 機能のキーワード: human leukocyte antigen, antigen presentation, immune system, t-cell receptor
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Membrane; Single-pass type I membrane protein: P18465; Secreted: P61769
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 45217.33

構造登録者

Vivian, J.P.,Illing, P.T.,McCluskey, J.,Rossjohn, J. (登録日: 2012-04-11, 公開日: 2012-05-30, 最終更新日: 2023-11-08)

主引用文献

Illing, P.T.,Vivian, J.P.,Dudek, N.L.,Kostenko, L.,Chen, Z.,Bharadwaj, M.,Miles, J.J.,Kjer-Nielsen, L.,Gras, S.,Williamson, N.A.,Burrows, S.R.,Purcell, A.W.,Rossjohn, J.,McCluskey, J.
Immune self-reactivity triggered by drug-modified HLA-peptide repertoire
Nature, 486:554-558, 2012

PubMed Abstract: Human leukocyte antigens (HLAs) are highly polymorphic proteins that initiate immunity by presenting pathogen-derived peptides to T cells. HLA polymorphisms mostly map to the antigen-binding cleft, thereby diversifying the repertoire of self-derived and pathogen-derived peptide antigens selected by different HLA allotypes. A growing number of immunologically based drug reactions, including abacavir hypersensitivity syndrome (AHS) and carbamazepine-induced Stevens-Johnson syndrome (SJS), are associated with specific HLA alleles. However, little is known about the underlying mechanisms of these associations, including AHS, a prototypical HLA-associated drug reaction occurring exclusively in individuals with the common histocompatibility allele HLA-B*57:01, and with a relative risk of more than 1,000 (refs 6, 7). We show that unmodified abacavir binds non-covalently to HLA-B*57:01, lying across the bottom of the antigen-binding cleft and reaching into the F-pocket, where a carboxy-terminal tryptophan typically anchors peptides bound to HLA-B*57:01. Abacavir binds with exquisite specificity to HLA-B*57:01, changing the shape and chemistry of the antigen-binding cleft, thereby altering the repertoire of endogenous peptides that can bind HLA-B*57:01. In this way, abacavir guides the selection of new endogenous peptides, inducing a marked alteration in 'immunological self'. The resultant peptide-centric 'altered self' activates abacavir-specific T-cells, thereby driving polyclonal CD8 T-cell activation and a systemic reaction manifesting as AHS. We also show that carbamazepine, a widely used anti-epileptic drug associated with hypersensitivity reactions in HLA-B*15:02 individuals, binds to this allotype, producing alterations in the repertoire of presented self peptides. Our findings simultaneously highlight the importance of HLA polymorphism in the evolution of pharmacogenomics and provide a general mechanism for some of the growing number of HLA-linked hypersensitivities that involve small-molecule drugs.

PubMed: 22722860
DOI: 10.1038/nature11147

実験手法

X-RAY DIFFRACTION (1.6 Å)