T-Cell Receptor CDR3 Loop Conformations in Solution Shift the Relative Vα-Vβ Domain Distributions
T-Cell Receptor CDR3 Loop Conformations in Solution Shift the Relative Vα-Vβ Domain Distributions
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DOI：
10.3389/fimmu.2020.01440
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发表时间：
2020-07-08
影响因子：
7.3
通讯作者：
Liedl, Klaus R.
中科院分区：
文献类型：
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作者：
Fernandez-Quintero, Monica L.;Pomarici, Nancy D.;Liedl, Klaus R.
t细胞受体是适应性免疫系统的重要组成部分，因为它们负责检测由主要组织相容性复合体（MHC）呈递的外来蛋白。这种亲和性主要由互补决定区（cdr）的结构和序列决定，其中CDR3环负责肽识别。我们提出了t细胞受体CDR3环的动力学分类与不同的环长度成规范和非规范溶液结构。通过分子动力学模拟，我们不仅对可用的x射线结构进行了采样，而且还观察到溶液中具有各种不同动力学极小值的更广泛的CDR3环系综。我们的结果强烈暗示，对于给定的CDR3环序列，必须考虑几个典型结构来表征这些环的构象多样性。我们建议的优势溶液结构可以通过包括溶液中存在的动力学最小结构来扩展可用正则簇的曲目。因此，CDR3环需要被表征为溶液中的构象系。此外，CDR3环的构象变化遵循构象选择的范式，因为实验确定的结合能力状态存在于没有抗原存在的预先存在的构象集合中。我们还确定了CDR3环之间的强相关性，并包括组合状态描述。此外，我们观察到CDR3环构象对相对的V α -V β域间取向有很强的依赖性，表明某些CDR3环状态有利于特定的界面取向。
T-cell receptors are an important part in the adaptive immune system as they are responsible for detecting foreign proteins presented by the major histocompatibility complex (MHC). The affinity is predominantly determined by structure and sequence of the complementarity determining regions (CDRs), of which the CDR3 loops are responsible for peptide recognition. We present a kinetic classification of T-cell receptor CDR3 loops with different loop lengths into canonical and non-canonical solution structures. Using molecular dynamics simulations, we do not only sample available X-ray structures, but we also observe a substantially broader CDR3 loop ensemble with various distinct kinetic minima in solution. Our results strongly imply, that for given CDR3 loop sequences several canonical structures have to be considered to characterize the conformational diversity of these loops. Our suggested dominant solution structures could extend the repertoire of available canonical clusters by including kinetic minimum structures present in solution. Thus, the CDR3 loops need to be characterized as conformational ensembles in solution. Furthermore, the conformational changes of the CDR3 loops follow the paradigm of conformational selection, because the experimentally determined binding competent state is present within this ensemble of pre-existing conformations without the presence of the antigen. We also identify strong correlations between the CDR3 loops and include combined state descriptions. Additionally, we observe a strong dependency of the CDR3 loop conformations on the relative V alpha-V beta interdomain orientations, revealing that certain CDR3 loop states favor specific interface orientations.