Garcia K C, Degano M, Pease L R, Huang M, Peterson P A, Teyton L, Wilson I A
Department of Molecular Biology and the Skaggs Institute of Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Science. 1998 Feb 20;279(5354):1166-72. doi: 10.1126/science.279.5354.1166.
The T cell receptor (TCR) inherently has dual specificity. T cells must recognize self-antigens in the thymus during maturation and then discriminate between foreign pathogens in the periphery. A molecular basis for this cross-reactivity is elucidated by the crystal structure of the alloreactive 2C TCR bound to self peptide-major histocompatibility complex (pMHC) antigen H-2Kb-dEV8 refined against anisotropic 3.0 angstrom resolution x-ray data. The interface between peptide and TCR exhibits extremely poor shape complementarity, and the TCR beta chain complementarity-determining region 3 (CDR3) has minimal interaction with the dEV8 peptide. Large conformational changes in three of the TCR CDR loops are induced upon binding, providing a mechanism of structural plasticity to accommodate a variety of different peptide antigens. Extensive TCR interaction with the pMHC alpha helices suggests a generalized orientation that is mediated by the Valpha domain of the TCR and rationalizes how TCRs can effectively "scan" different peptides bound within a large, low-affinity MHC structural framework for those that provide the slight additional kinetic stabilization required for signaling.
T细胞受体（TCR）本质上具有双重特异性。T细胞在成熟过程中必须在胸腺中识别自身抗原，然后在周围环境中区分外来病原体。与自身肽-主要组织相容性复合体（pMHC）抗原H-2Kb-dEV8结合的同种异体反应性2C TCR的晶体结构，针对各向异性3.0埃分辨率的X射线数据进行了优化，阐明了这种交叉反应性的分子基础。肽与TCR之间的界面显示出极差的形状互补性，并且TCRβ链互补决定区3（CDR3）与dEV8肽的相互作用极小。结合时会诱导TCR的三个CDR环发生大的构象变化，提供了一种结构可塑性机制，以适应各种不同的肽抗原。TCR与pMHCα螺旋的广泛相互作用表明了一种由TCR的Vα结构域介导的普遍取向，并解释了TCR如何能够有效地“扫描”结合在大型、低亲和力MHC结构框架内的不同肽，以寻找那些为信号传导提供轻微额外动力学稳定性的肽。
