Sulfamethoxazole induces a switch mechanism in T cell receptors containing TCRVβ20-1, altering pHLA recognition

PLoS One. 2013 Oct 7;8(10):e76211. doi: 10.1371/journal.pone.0076211. eCollection 2013.

Abstract

T cell receptors (TCR) containing Vβ20-1 have been implicated in a wide range of T cell mediated disease and allergic reactions, making it a target for understanding these. Mechanics of T cell receptors are largely unexplained by static structures available from x-ray crystallographic studies. A small number of molecular dynamic simulations have been conducted on TCR, however are currently lacking either portions of the receptor or explanations for differences between binding and non-binding TCR recognition of respective peptide-HLA. We performed molecular dynamic simulations of a TCR containing variable domain Vβ20-1, sequenced from drug responsive T cells. These were initially from a patient showing maculopapular eruptions in response to the sulfanilamide-antibiotic sulfamethoxazole (SMX). The CDR2β domain of this TCR was found to dock SMX with high affinity. Using this compound as a perturbation, overall mechanisms involved in responses mediated by this receptor were explored, showing a chemical action on the TCR free from HLA or peptide interaction. Our simulations show two completely separate modes of binding cognate peptide-HLA complexes, with an increased affinity induced by SMX bound to the Vβ20-1. Overall binding of the TCR is mediated through a primary recognition by either the variable β or α domain, and a switch in recognition within these across TCR loops contacting the peptide and HLA occurs when SMX is present in the CDR2β loop. Large binding affinity differences are induced by summed small amino acid changes primarily by SMX modifying only three critical CDR2β loop amino acid positions. These residues, TYRβ57, ASPβ64, and LYSβ65 initially hold hydrogen bonds from the CDR2β to adjacent CDR loops. Effects from SMX binding are amplified and traverse longer distances through internal TCR hydrogen bonding networks, controlling the overall TCR conformation. Thus, the CDR2β of Vβ20-1 acts as a ligand controlled switch affecting overall TCR binding affinity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Anti-Infective Agents / adverse effects
  • Anti-Infective Agents / chemistry
  • Anti-Infective Agents / metabolism
  • Binding Sites
  • Binding, Competitive
  • Crystallography, X-Ray
  • Drug Eruptions / etiology
  • Drug Eruptions / metabolism
  • HLA Antigens / chemistry*
  • HLA Antigens / metabolism
  • HLA-DR beta-Chains / chemistry
  • HLA-DR beta-Chains / metabolism
  • Humans
  • Hydrogen Bonding
  • Models, Molecular
  • Molecular Dynamics Simulation
  • Molecular Sequence Data
  • Peptides / chemistry
  • Peptides / metabolism
  • Principal Component Analysis
  • Protein Binding
  • Protein Structure, Tertiary
  • Receptors, Antigen, T-Cell / chemistry*
  • Receptors, Antigen, T-Cell / metabolism
  • Receptors, Antigen, T-Cell, alpha-beta / chemistry*
  • Receptors, Antigen, T-Cell, alpha-beta / metabolism
  • Sulfamethoxazole / adverse effects
  • Sulfamethoxazole / chemistry*
  • Sulfamethoxazole / metabolism
  • Thermodynamics

Substances

  • Anti-Infective Agents
  • HLA Antigens
  • HLA-DR beta-Chains
  • Peptides
  • Receptors, Antigen, T-Cell
  • Receptors, Antigen, T-Cell, alpha-beta
  • Sulfamethoxazole

Grants and funding

This study was supported by the Swiss National Science Foundation, supporting grant number SNF 310030_129828/1, and Swiss Center of Human Toxicology (SCAHT). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.