6CX7

Structure of alpha-GSA[12,6P] bound by CD1d and in complex with the Va14Vb8.2 TCR

Summary for 6CX7

• Entry DOI: 10.2210/pdb6cx7/pdb
• Descriptor: Chimeric T cell antigen receptor alpha chain Va14,Va24,Ja18, Chimeric T cell antigen receptor beta chain Vb8.2, vb11, Antigen-presenting glycoprotein CD1d1, ... (9 entities in total)
• Functional Keywords: immune system, antigen-presentation, tcr, mhc-fold
• Biological source: Mus musculus (Mouse); More
• Total number of polymer chains: 4
• Total formula weight: 96470.91

Authors

Wang, J.,Zajonc, D. (deposition date: 2018-04-02, release date: 2019-04-10, Last modification date: 2023-10-04)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.6 Å)