[48]), as well as studies of the intrinsic flexibility of TCR CDR loops and peptides bound to MHC molecules (e.g. CDR3 loops, although in some cases Lycoctonine the germline-encoded CDR1 and CDR2 loops shift in magnitudes that approximate those of the CDR3 loops. Intriguingly, the smallest shifts are in the germline-encoded loops of the -chain, consistent with recent suggestions that the TCR domain may drive ligand recognition. strong class=”kwd-title” Keywords: conformational selection, cross-reactivity, crystal structure, induced fit, peptideCMHC (pMHC), T-cell receptor (TCR) strong class=”kwd-title” Abbreviations: CDR, complementarity determining region; MBP, myelin basic protein; pMHC, peptideCMHC; TCR, T-cell receptor INTRODUCTION TCRs (T-cell receptors) expressed by CD4+ or CD8+ T-cells are responsible for recognizing antigenic peptides bound and presented by class I or class II MHC proteins. Recognition Rabbit polyclonal to ABCA6 of a pMHC (peptideCMHC) complex by a TCR is required for the initiation and propagation of a cellular immune response, as well as the generation and maintenance of the body’s T-cell repertoire. In some regards, TCRs are similar to antibodies. Notably, TCR antigen-binding sites are composed of multiple CDR (complementarity determining region) loops generated via recombination processes similar to those used in antibody generation. However, one of the many differences between antibodies and TCRs is the nature of the ligand recognized. Whereas antibodies recognize linear or non-linear epitopes of seemingly unlimited chemical and structural diversity, TCRs recognize a composite surface consisting of elements of the antigenic peptide as well as the -helices of the MHC peptide-binding groove. Thus, unlike antibodies, the ligand for the TCR consists of both self (the MHC) and non-self (the peptide) components. TCRs are also cross-reactive, capable of recognizing multiple peptides bound to one or more MHC molecules. TCR cross-reactivity is necessary for T-cell development and maintenance and is crucial given the fixed size of the T-cell repertoire relative to the vast universe Lycoctonine of potential antigens [1C3]. Moreover, TCR cross-reactivity has been implicated in numerous autoimmune pathologies and is an underlying cause of transplant rejection. The structural and physical properties of TCRs and their complexes with pMHC molecules have been reviewed several times, with perspectives provided previously by Garcia and Adams [4] and Rudolph et al. [5]. Yet even since these contributions, the TCRCpMHC structural database has grown considerably. With regards to TCR cross-reactivity, the number of TCRs, both bound and free, for which structural information is available is now large enough to permit general conclusions to be drawn about conformational changes in TCR antigen-binding sites and their roles in receptor specificity and cross-reactivity. In the present paper, we review the database of TCRs whose structures have been determined both bound and free, focusing on molecular flexibility and dynamics. We primarily discuss TCR CDR loops, initially examining how loop flexibility and dynamics might influence TCR specificity and cross-reactivity, but also comparing loop positions in cases where the same receptor is bound to different ligands. Overall, we conclude that, although TCR conformational Lycoctonine changes do broaden TCR reactivity, with few exceptions, the underlying motions do not reflect the large-scale flexibility which is characteristic of disordered regions; rather, the motions tend to be rigid-body shifts facilitated mostly by hinge-bending movements. The largest shifts occur in the randomly generated CDR3 and CDR3 loops, with the germline loops typically making relatively minor rigid-body adjustments. Interestingly, we observe that the germline-encoded CDR1 and CDR2 loops of the TCR -chain alter their conformations the least upon recognition of pMHC, consistent with a role for the -chain in driving the recognition of MHC as hypothesized recently [6C8]. Finally, we highlight emerging principles in the basic biophysics of proteinCprotein recognition, discussing the similarities and differences between induced-fit binding and conformational selection from a pre-existing equilibria, concluding with a call for more sophisticated experiments capable of fully resolving binding mechanisms and characterizing protein conformational dynamics. SUMMARY OF CONFORMATIONAL SHIFTS IN TCR CDR LOOPS OCCURRING UPON BINDING In the mid-to-late 1990s, binding studies performed with soluble ectodomains of TCRs and class I or class II pMHC complexes indicated that TCRs bind pMHC weakly with low association rates, typically 105 M?1s?1 [9]. Rates of this magnitude are lower than expected for a geometrically.