TcR recognition of the MHC-peptide dimer: Structural properties of a ternary complex

George Vasmatzis, James Cornette, Ugur Sezerman, Charles DeLisi

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


We have developed a method that utilizes site-specific mutation data, sequence analysis, immunological data and free-energy minimization, to determine structural features of the ternary complex formed by the T-cell receptor (TcR) and the class I major histocompatibility complex (MHC) molecule bound by peptide. The analysis focuses on the mouse K(d) MHC system, for which a large set of clones with sequenced T-cell receptors is available for specific peptides. The general philosophy is to reduce the uncertainties and computation time in a free-energy minimization procedure by identifying and imposing experimental constraints. In addition to assessing compatibility with various kinds of immunological data, we are particularly interested in differentiating the structural features peculiar to this particular system from generic features, and in ascertaining the robustness of the structure; i.e. determining, in so far as possible, the variations in the structure that leave its compatibility with experiment unaltered from those that do not. This last is equivalent to recognizing that certain features of the model are presented with a reasonable degree of confidence, while others remain highly tentative. The central conclusion in the former category is a placement of the TcR on the K(d) peptide complex, which has its β2, β3 and α3 loops (i.e. the second and third complementarity-determining region of the TcR β chain, and the third complementarity-determining region of the a chain) covering the peptide; the α1 and α2 loops covering the MHC α1 helix; the α2 loop interacting with residues on the MHC β sheet; and the β1 and (part of) the β2 loops covering the at MHC helix. More specifically, our findings include the following. (1) A highly conserved histidine residue in the first complementarity-determining region of the TcR β chain (P:CDR1) points outward and interacts with highly conserved side-chains on the MHC α2 helix. (2) The amino-terminal portion of the β2 loop interacts with the carboxyl portion of the peptide. A particularly important interaction is K4 of the loop interacting with E8 of the peptide. (3) Charged side-chains of the 11-residue TcR at loop interact with conserved charged side-chains at positions 44, 58, 61 and 68 on the MHC. (4) The TcR β3 loop interacts with the amino-terminal part of the peptide, up through position 4. (5) the TcR as loop interacts with the central portion of the peptide and stacks against the β2 loop. (6) Because of the interaction between the β2 loop and the peptide, and stacking of β2 on α3, α3 gene and V(β) gene selection can be correlated. (7) Using the topology of the recently solved TcR a chain we predict that the α2 loop interacts with the loop on the MHC β sheet floor, which encompasses residues 42 to 44.

Original languageEnglish (US)
Pages (from-to)72-89
Number of pages18
JournalJournal of Molecular Biology
Issue number1
StatePublished - Aug 9 1996


  • Class I MHC
  • Local moves
  • T-cell receptor
  • TcR-MHC orientation
  • Ternary complex

ASJC Scopus subject areas

  • Molecular Biology
  • Biophysics
  • Structural Biology


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