• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文OA文献 >Sulfamethoxazole induces a switch mechanism in T cell receptors containing TCRVβ20-1, altering pHLA recognition
【2h】

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

机译：磺胺甲恶唑诱导含有TCRVβ20-1的T细胞受体的转换机制，从而改变pHLA的识别

代理获取
本网站仅为用户提供外文OA文献查询和代理获取服务，本网站没有原文。下单后我们将采用程序或人工为您竭诚获取高质量的原文，但由于OA文献来源多样且变更频繁，仍可能出现获取不到、文献不完整或与标题不符等情况，如果获取不到我们将提供退款服务。请知悉。
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

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.
机译：包含Vβ20-1的T细胞受体（TCR）已与多种T细胞介导的疾病和变态反应有关，使其成为了解这些的靶标。 T细胞受体的力学在很大程度上无法通过X射线晶体学研究获得的静态结构进行解释。已经对TCR进行了少量的分子动力学模拟，但是目前缺乏受体的任何部分，也没有解释对相应肽HLA的结合和非结合TCR识别之间差异的解释。我们对包含从药物反应性T细胞测序的可变域Vβ20-1的TCR进行了分子动力学模拟。这些最初来自对磺胺类抗生素抗生素磺胺甲恶唑（SMX）有反应的斑丘疹爆发的患者。发现该TCR的CDR2β结构域以高亲和力对接SMX。使用该化合物作为扰动，探讨了由该受体介导的反应所涉及的总体机制，显示了对TCR的化学作用，没有HLA或肽相互作用。我们的模拟显示了结合同源肽-HLA复合物的两种完全独立的模式，SMX结合至Vβ20-1诱导了更高的亲和力。 TCR的整体结合是通过可变β或α结构域的一级识别介导的，当SMX存在于CDR2β环中时，跨接触肽和HLA的TCR环中的识别转换就会发生。较大的结合亲和力差异是由主要通过SMX仅修饰三个关键CDR2β环氨基酸位置的总氨基酸小变化引起的。这些残基TYRβ57，ASPβ64和LYSβ65最初具有从CDR2β到相邻CDR环的氢键。 SMX结合产生的效应被放大，并通过内部TCR氢键网络穿越更长的距离，从而控制总体TCR构象。因此，Vβ20-1的CDR2β充当受配体控制的开关，影响总体TCR结合亲和力。

著录项

相似文献

  • 外文文献
  • 专利
代理获取

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号