5NMG

868 TCR in complex with HLA A02 presenting SLYFNTIAVL

Summary for 5NMG

• Entry DOI: 10.2210/pdb5nmg/pdb
• Descriptor: HLA class I histocompatibility antigen, A-2 alpha chain, Beta-2-microglobulin, Gag protein, ... (9 entities in total)
• Functional Keywords: mhc, tcr, cd8+, immune system
• Biological source: Homo sapiens (Human); More
• Cellular location: Membrane; Single-pass type I membrane protein: P01892; Secreted . Note=(Microbial infection) In the presence of M: P61769
• Total number of polymer chains: 10
• Total formula weight: 190502.78

Authors

Rizkallah, P.J.,Cole, D.K.,Fuller, A.,Sewell, A.K. (deposition date: 2017-04-05, release date: 2017-11-15, Last modification date: 2024-10-09)

Primary citation

Cole, D.K.,Fuller, A.,Dolton, G.,Zervoudi, E.,Legut, M.,Miles, K.,Blanchfield, L.,Madura, F.,Holland, C.J.,Bulek, A.M.,Bridgeman, J.S.,Miles, J.J.,Schauenburg, A.J.A.,Beck, K.,Evavold, B.D.,Rizkallah, P.J.,Sewell, A.K.
Dual Molecular Mechanisms Govern Escape at Immunodominant HLA A2-Restricted HIV Epitope.
Front Immunol, 8:1503-1503, 2017

PubMed Abstract: Serial accumulation of mutations to fixation in the SLYNTVATL (SL9) immunodominant, HIV p17 Gag-derived, HLA A2-restricted cytotoxic T lymphocyte epitope produce the SLFNTIAVL triple mutant "ultimate" escape variant. These mutations in solvent-exposed residues are believed to interfere with TCR recognition, although confirmation has awaited structural verification. Here, we solved a TCR co-complex structure with SL9 and the triple escape mutant to determine the mechanism of immune escape in this eminent system. We show that, in contrast to prevailing hypotheses, the main TCR contact residue is 4N and the dominant mechanism of escape is not lack of TCR engagement. Instead, mutation of solvent-exposed residues in the peptide destabilise the peptide-HLA and reduce peptide density at the cell surface. These results highlight the extraordinary lengths that HIV employs to evade detection by high-affinity TCRs with a broad peptide-binding footprint and necessitate re-evaluation of this exemplar model of HIV TCR escape.

PubMed: 29209312
DOI: 10.3389/fimmu.2017.01503

Experimental method

X-RAY DIFFRACTION (2.75 Å)