6CXA

Structure of alpha-GSA[20,6P] bound by CD1d and in complex with the Va14Vb8.2 TCR

6CXA の概要

• エントリーDOI: 10.2210/pdb6cxa/pdb
• 分子名称: Antigen-presenting glycoprotein CD1d1, Beta-2-microglobulin, Chimeric T cell antigen receptor alpha chain Va14,Va24,Ja18, ... (9 entities in total)
• 機能のキーワード: immune system, antigen-presentation, tcr, mhc-fold
• 由来する生物種: Mus musculus (Mouse); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 96627.99

構造登録者

Wang, J.,Zajonc, D. (登録日: 2018-04-02, 公開日: 2019-04-10, 最終更新日: 2024-10-16)

主引用文献

Wang, J.,Guillaume, J.,Janssens, J.,Remesh, S.G.,Ying, G.,Bitra, A.,Van Calenbergh, S.,Zajonc, D.M.
A molecular switch in mouse CD1d modulates natural killer T cell activation by alpha-galactosylsphingamides.
J.Biol.Chem., 294:14345-14356, 2019

PubMed Abstract: Type I natural killer T (NKT) cells are a population of innate like T lymphocytes that rapidly respond to α-GalCer presented by CD1d via the production of both pro- and anti-inflammatory cytokines. While developing novel α-GalCer analogs that were meant to be utilized as potential adjuvants because of their production of pro-inflammatory cytokines (Th1 skewers), we generated α-galactosylsphingamides (αGSA). Surprisingly, αGSAs are not potent antigens despite their strong T-cell receptor (TCR)-binding affinities. Here, using surface plasmon resonance (SPR), antigen presentation assays, and X-ray crystallography (yielding crystal structures of 19 different binary (CD1d-glycolipid) or ternary (CD1d-glycolipid-TCR) complexes at resolutions between 1.67 and 2.85 Å), we characterized the biochemical and structural details of αGSA recognition by murine NKT cells. We identified a molecular switch within murine (m)CD1d that modulates NKT cell activation by αGSAs. We found that the molecular switch involves a hydrogen bond interaction between Tyr-73 of mCD1d and the amide group oxygen of αGSAs. We further established that the length of the acyl chain controls the positioning of the amide group with respect to the molecular switch and works synergistically with Tyr-73 to control NKT cell activity. In conclusion, our findings reveal important mechanistic insights into the presentation and recognition of glycolipids with polar moieties in an otherwise apolar milieu. These observations may inform the development αGSAs as specific NKT cell antagonists to modulate immune responses.

PubMed: 31391251
DOI: 10.1074/jbc.RA119.009963

実験手法

X-RAY DIFFRACTION (2.65 Å)