An Engineered Switch in T Cell Receptor Specificity Leads to an Unusual but Functional Binding Geometry
An Engineered Switch in T Cell Receptor Specificity Leads to an Unusual but Functional Binding Geometry
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DOI：
10.1016/j.str.2016.04.011
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发表时间：
2016-07-06
期刊：
影响因子：
5.7
通讯作者：
Baker, Brian M.
中科院分区：
文献类型：
--
作者：
Harris, Daniel T.;Singh, Nishant K.;Baker, Brian M.
利用不同的结合位点，T细胞受体（TCR）特异性识别由外源肽和主要组织相容性复合体蛋白（MHC）组成的复合配体。为了帮助理解TCR特异性的决定因素，我们研究了亲本和工程受体，其肽特异性已通过分子进化转换。改变的特异性与TCR结合几何结构的显著变化相关，但这并不影响TCR以抗原特异性方式发出信号的能力。结合和特异性的决定因素分布在生殖系和高变环中的接触和非接触残基中，并且包括使ab TCR偏向特定结合模式的关键TCR-MHC相互作用的破坏。序列适应度景观确定了进一步增强特异性的其他突变。我们的研究结果表明，TCR特异性产生于整个界面的许多位点的分布式作用，具有重要意义的工程治疗TCR与新的和功能性的识别特性。
Utilizing a diverse binding site, T cell receptors (TCRs) specifically recognize a composite ligand comprised of a foreign peptide and a major histocompatibility complex protein (MHC). To help understand the determinants of TCR specificity, we studied a parental and engineered receptor whose peptide specificity had been switched via molecular evolution. Altered specificity was associated with a significant change in TCR-binding geometry, but this did not impact the ability of the TCR to signal in an antigen-specific manner. The determinants of binding and specificity were distributed among contact and non-contact residues in germline and hypervariable loops, and included disruption of key TCR-MHC interactions that bias ab TCRs toward particular binding modes. Sequence-fitness landscapes identified additional mutations that further enhanced specificity. Our results demonstrate that TCR specificity arises from the distributed action of numerous sites throughout the interface, with significant implications for engineering therapeutic TCRs with novel and functional recognition properties.