Document Detail

Structural and dynamic control of T-cell receptor specificity, cross-reactivity, and binding mechanism.
MedLine Citation:
PMID:  23046120     Owner:  NLM     Status:  MEDLINE    
Over the past two decades, structural biology has shown how T-cell receptors engage peptide/major histocompatibility complex (MHC) complexes and provided insight into the mechanisms underlying antigen specificity and cross-reactivity. Here we review and contextualize our contributions, which have emphasized the influence of structural changes and molecular flexibility. A repeated observation is the presence of conformational melding, in which the T-cell receptor (TCR), peptide, and in some cases, MHC protein cooperatively adjust in order for recognition to proceed. The structural changes reflect the intrinsic dynamics of the unligated proteins. Characterization of the dynamics of unligated TCR shows how binding loop motion can influence TCR cross-reactivity as well as specificity towards peptide and MHC. Examination of peptide dynamics indicates not only peptide-specific variation but also a peptide dependence to MHC flexibility. This latter point emphasizes that the TCR engages a composite peptide/MHC surface and that physically the receptor makes little distinction between the peptide and MHC. Much additional evidence for this can be found within the database of available structures, including our observations of a peptide dependence to the TCR binding mode and structural compensations for altered interatomic interactions, in which lost TCR-peptide interactions are replaced with TCR-MHC interactions. The lack of a hard-coded physical distinction between peptide and MHC has implications not only for specificity and cross-reactivity but also the mechanisms underlying MHC restriction as well as attempts to modulate and control TCR recognition.
Brian M Baker; Daniel R Scott; Sydney J Blevins; William F Hawse
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Review    
Journal Detail:
Title:  Immunological reviews     Volume:  250     ISSN:  1600-065X     ISO Abbreviation:  Immunol. Rev.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-10-10     Completed Date:  2013-02-25     Revised Date:  2013-12-03    
Medline Journal Info:
Nlm Unique ID:  7702118     Medline TA:  Immunol Rev     Country:  England    
Other Details:
Languages:  eng     Pagination:  10-31     Citation Subset:  IM    
Copyright Information:
© 2012 John Wiley & Sons A/S.
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MeSH Terms
Antigens / chemistry*,  immunology,  metabolism
Binding Sites
Cross Reactions
Lymphocyte Activation
Major Histocompatibility Complex / immunology*
Models, Molecular
Peptides / chemistry*,  immunology,  metabolism
Protein Binding
Protein Conformation
Receptors, Antigen, T-Cell / chemistry*,  immunology,  metabolism
T-Cell Antigen Receptor Specificity
T-Lymphocytes / cytology,  immunology*,  metabolism
Grant Support
Reg. No./Substance:
0/Antigens; 0/Peptides; 0/Receptors, Antigen, T-Cell

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