Disparate degrees of hypervariable loop flexibility control T-cell receptor cross-reactivity, specificity, and
Daniel R Scott1, Oleg Y Borbulevych, Kurt H Piepenbrink
1Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.
Journal of Molecular Biology
|October 25, 2011
Summary
T-cell receptor (TCR) loop flexibility influences antigen recognition. CDR3β loop flexibility allows broad ligand binding, while CDR3α loop flexibility confers specificity, revealing complex TCR binding mechanisms.
Area of Science:
- Immunology
- Structural Biology
- Computational Biology
Background:
- T-cell receptors (TCRs) recognize peptide-MHC complexes.
- TCR cross-reactivity is partly attributed to loop flexibility, but direct studies are limited.
Purpose of the Study:
- To investigate the role of binding loop flexibility in TCR A6 function.
- To elucidate the mechanisms of TCR binding, cross-reactivity, and specificity.
Main Methods:
- Crystallography
- Spectroscopy
- Computational analysis of energy landscapes
Main Results:
- Flexibility in CDR3α and CDR3β loops significantly impacts TCR binding and cross-reactivity.
- CDR3β exhibits a broad energy landscape, enabling conformational sampling for diverse ligands.
- CDR3α shows a rugged energy landscape, promoting specificity for a narrower range of peptides and MHC.
Conclusions:
- TCR binding involves a blend of conformational selection and induced fit mechanisms.
- Loop dynamics, particularly CDR3 flexibility, are crucial for determining TCR specificity and cross-reactivity.
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