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Related Experiment Videos

TCR binding to peptide-MHC stabilizes a flexible recognition interface.

B E Willcox1, G F Gao, J R Wyer

  • 1Nuffield Department of Clinical Medicine, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom.

Immunity
|April 16, 1999
PubMed
Summary

T-cell receptor (TCR) binding to peptide-MHC involves conformational changes and reduced disorder, explaining low affinity and cross-reactivity. This flexibility in TCRs and peptide-MHC is key to antigen recognition.

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Obituary.

HLA·2016

Area of Science:

  • Immunology
  • Biochemistry
  • Structural Biology

Background:

  • T-cell receptors (TCRs) bind peptide-MHC ligands with low affinity, slow kinetics, and high cross-reactivity.
  • Understanding the biophysical basis of this interaction is crucial for immunology and drug development.

Purpose of the Study:

  • To kinetically and thermodynamically analyze the binding of two TCRs to their peptide-MHC ligands.
  • To elucidate the molecular mechanisms underlying TCR-pMHC interactions, including affinity, kinetics, and cross-reactivity.

Main Methods:

  • Kinetic analysis of TCR-peptide-MHC interactions.
  • Thermodynamic analysis of TCR-peptide-MHC binding.
  • Computational modeling to assess conformational flexibility.

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Main Results:

  • Significant activation energy barriers were observed for both association and dissociation, indicating required conformational adjustments.
  • Low binding affinity results from highly unfavorable entropic effects, suggesting substantial disorder reduction upon binding.
  • Evidence points to flexible binding surfaces in TCR and/or peptide-MHC that stabilize upon complex formation.

Conclusions:

  • Conformational flexibility in TCR-peptide-MHC interactions is a key feature contributing to their functional characteristics.
  • This flexibility likely underlies the observed cross-reactivity in antigen recognition by TCRs.
  • The findings provide insights into the molecular basis of adaptive immunity and potential therapeutic strategies.