Solution mapping of T cell receptor docking footprints on peptide-MHC

Luca Varani, Alexander J. Bankovich, Corey W. Liu, Leremy A. Colf, Lindsay L. Jones, David M. Kranz, Joseph D. Puglisi, K. Christopher Garcia

Research output: Contribution to journalArticle

Abstract

T cell receptor (TCR) recognition of peptide-MHC (pMHC) is central to the cellular immune response. A large database of TCR-pMHC structures is needed to reveal general structural principles, such as whether the repertoire of TCR/MHC docking modes is dictated by a "recognition code" between conserved elements of the TCR and MHC genes. Although ≈17 cocrystal structures of unique TCR-pMHC complexes have been determined, cocrystallization of soluble TCR and pMHC remains a major technical obstacle in the field. Here we demonstrate a strategy, based on NMR chemical shift mapping, that permits rapid and reliable analysis of the solution footprint made by a TCR when binding onto the pMHC surface. We mapped the 2C TCR binding interaction with its allogeneic ligand H-2Ld-QL9 and identified a group of NMR-shifted residues that delineated a clear surface of the MHC that we defined as the TCR footprint. We subsequently found that the docking footprint described by NMR shifts was highly accurate compared with a recently determined high-resolution crystal structure of the same complex. The same NMR footprint analysis was done on a high-affinity mutant of the TCR. The current work serves as a foundation to explore the molecular dynamics of pMHC complexes and to rapidly determine the footprints of many Ld-specific TCRs.

Original languageEnglish (US)
Pages (from-to)13080-13085
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number32
DOIs
StatePublished - Aug 7 2007

Keywords

  • Cellular immunity
  • Chemical shift mapping
  • Dynamics
  • NMR
  • Protein-protein interaction

ASJC Scopus subject areas

  • General

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  • Cite this

    Varani, L., Bankovich, A. J., Liu, C. W., Colf, L. A., Jones, L. L., Kranz, D. M., Puglisi, J. D., & Garcia, K. C. (2007). Solution mapping of T cell receptor docking footprints on peptide-MHC. Proceedings of the National Academy of Sciences of the United States of America, 104(32), 13080-13085. https://doi.org/10.1073/pnas.0703702104