Department of Microbiology and Immunology, University of Illinois, Chicago, IL, 60612, USA.
Center for Quantum Technology Research and Key Laboratory of Advanced Optoelectronic Quantum Architecture and Measurements, School of Physics, Beijing Institute of Technology, Beijing, 100081, China.
Nat Commun. 2023 Aug 18;14(1):5020. doi: 10.1038/s41467-023-40736-6.
Studies have suggested that MHC class I (MHC I) molecules fluctuate rapidly between numerous conformational states and these motions support peptide sampling. To date, MHC I intermediates are largely uncharacterized experimentally and remain elusive. Here, we present x-ray crystal structures of HLA-B8 loaded with 20mer peptides that show pronounced distortions at the N-terminus of the groove. Long stretches of N-terminal amino acid residues are missing in the electron density maps creating an open-ended groove. Our structures also reveal highly unusual features in MHC I-peptide interaction at the N-terminus of the groove. Molecular dynamics simulations indicate that the complexes have varying degrees of conformational flexibility in a manner consistent with the structures. We suggest that our structures have captured the remarkable molecular dynamics of MHC I-peptide interaction. The visualization of peptide-dependent conformational motions in MHC I is a major step forward in our conceptual understanding of dynamics in high-affinity peptide selection.
研究表明，MHC I 分子在多种构象状态之间快速波动，这些运动支持肽的采样。迄今为止，MHC I 中间体在很大程度上尚未得到实验表征，仍然难以捉摸。在这里，我们展示了 HLA-B8 负载 20 mer 肽的 x 射线晶体结构，这些结构在凹槽的 N 末端显示出明显的扭曲。在电子密度图中，较长的 N 末端氨基酸残基缺失，形成了一个无末端的凹槽。我们的结构还揭示了凹槽 N 末端 MHC I-肽相互作用中非常不寻常的特征。分子动力学模拟表明，这些复合物在结构上具有不同程度的构象灵活性。我们认为，我们的结构捕捉到了 MHC I-肽相互作用的显著分子动力学。MHC I 中依赖于肽的构象运动的可视化是我们对高亲和力肽选择动力学的概念理解的重要一步。
