Molecular modeling of a T-cell receptor bound to a major histocompatibility complex molecule: Implications for T-cell recognition

Abstract

The main functions of the T-cell receptor (TCR) involve its specific interaction with short and linear antigenic peptides bound to the major histocompatibility complex (MHC) molecules. In the absence of a 3D structure for TCR and for the TCR/peptide/MHC complex, several attempts to characterize the structural components of the TCR/peptide/MHC interaction have been made. However, this subject is still troublesome.In this paper a computer-based 3D model for a TCR/peptide/MHC complex (5C.C7/moth cytochrome c [MCC] peptide 93-103/I-Ek) was obtained. The complex surface shows a high complementarity between the 5C.C7 structure and the peptide/I-Ek molecule. The mapping of residues involved in the TCR/peptide/MHC interaction shows close agreement with mutational experiments (Jorgensen JL, Reay PA, Ehrich EW, Davis MM, 1992b, Annu Rev Immunol10:835-873). Moreover, the results are consistent with a recent variability analysis of TCR sequences using three variability indexes (Almagro JC, Zenteno-Cuevas R, Vargas-Madrazo E, Lara-Ochoa F, 1995b, Int J Pept Protein Res 45:180-186). Accordingly, the 3D model of the 5C.C7/MCC peptide 93-103/I-Ek complex provides a framework to generate testable hypotheses about TCR recognition. Thus, starting from this model, the role played by each loop that forms the peptide/MHC binding site of the TCR is discussed. Keywords: TCR/peptide/MHC interaction complex; variability analysisThe specificity of the immune system is related to two protein families: Igs and TCRs. Igs directly recognize, via their V, and V, domains, the 3D structure of native antigenic proteins in solution (Davies et al., 1990), whereas TCRs recognize, via their V, and V, domains, short antigenic peptides bound to the MHC molecules (Davis, 1990). At present, significant advances have been made in the structural characterization of antigenic recognition mediated by Igs (Davies et al., 1990;Wilson & Stanfield, 1993;Padlan, 1994). In contrast, the nature of the interaction between TCRs and peptide-MHC complexes is poorly understood (Jorgensen et al., 1992b). This is partly due to the Reprint requests to: Juan C. Almagro, Instituto de Quimica, Universidad Nacional Autonoma de Mexico, Circuito Exterior, Ciudad Universitaria, C.P. lack of an experimental 3D structure for TCRs and for TCR/ peptide/MHC complexes.In the absence of 3D structures for TCRs, sequence analysis of their V domains shows that the V,/V, dimer has a framework structure that is very close to the Fv fragment of Igs (Novotny et al., 1986;Chothia et al., 1988). Further comparison has structurally assigned the six hypervariable loops that form the antigen-binding site of Igs to the binding site of TCRs (Chothia et al., 1988), termed a l , a2, and a3 for the V,, and 01, 02, and 03 for the V, in TCRs.Genetically, oll and a 2 are encoded by the V, gene, whereas a 3 is produced by the recombination of an additional gene segment: J a (Davis, 1990). In a similar way 01 and 02 are encoded by the V, gene, whereas 03 is a result of the recombination of two add...

Use of T cell receptor/HLA-DRB1*04 molecular modeling to predict site-specific interactions for the DR shared epitope associated with rheumatoid arthritis

“…There were 6 hydrogen bonds between the TCR and HA peptide (see Table 1), including 2 that were part of a salt bridge between CDR3P El03 and K310 of the HA peptide. However, the alignment of our TCR and MHC molecules in the trimolecular complex was oriented -180" from that reported by Jorgensen et a1 (46) and from that in another model of this TCR-class I1 MHC-peptide complex (5C.C7/1-Ek/moth cytochrome c) (25). However, the alignment of our TCR and MHC molecules in the trimolecular complex was oriented -180" from that reported by Jorgensen et a1 (46) and from that in another model of this TCR-class I1 MHC-peptide complex (5C.C7/1-Ek/moth cytochrome c) (25).…”

“…Due to this similarity, previous TCR models derived from immunoglobulin structures have been useful in describing general features of TCR recognition of the MHC-peptide complex (20,(23)(24)(25). Due to this similarity, previous TCR models derived from immunoglobulin structures have been useful in describing general features of TCR recognition of the MHC-peptide complex (20,(23)(24)(25).…”

Topology of T cell receptor-peptide/class I MHC interaction defined by charge reversal complementation and functional analysis

“…The results of the two genetic analyses of class II MHC-restricted TCRs offer a similar topology of interaction to that deduced in this study for the N15 and N26 class I MHC-restricted TCRs with Va overlapping the b1 helix and Vb overlapping the a1 helix. The topology of 5C.C7 interaction with its ligand ®ts well with recent molecular modeling results (Almagro et al, 1995). On the other hand, less direct approaches using class II restricted T cell clones have given con¯icting results (Wucherpfennig et al, 1995;Brawley & Concannon, 1996).…”

T-Cell Receptors Binding Orientation over Peptide/MHC Class I Is Driven by Long-Range Interactions

“…Molecular modeling methods tried to address in silico the question of TCR binding mode prediction in various ways, including manual orientation based on experimental data [40], homology modeling [41] [7], or protein-protein docking (private communication). Recently, the study from Roomp et al [4] presented an algorithm dedicated to TCR/pMHC interaction that quite reliably predicted the contacts between the pMHC and the CDR loops, using a training set of existing crystal structures, paving the road for in silico TCR binding mode prediction.…”