Department of Structural and Chemical Biology, Centre for Biological Research Margarita Salas, CIB-CSIC, C/ Ramiro de Maeztu, 9, 28040, Madrid, Spain.
Chemistry. 2021 Nov 5;27(62):15406-15425. doi: 10.1002/chem.202102995. Epub 2021 Oct 12.
The Toll-like receptor 4 (TLR4)/myeloid differentiation factor 2 (MD-2) innate immunity system is a membrane receptor of paramount importance as therapeutic target. Its assembly, upon binding of Gram-negative bacteria lipopolysaccharide (LPS), and also dependent on the membrane composition, finally triggers the immune response cascade. We have combined ab-initio calculations, molecular docking, all-atom molecular dynamics simulations, and thermodynamics calculations to provide the most realistic and complete 3D models of the active full TLR4 complex embedded into a realistic membrane to date. Our studies give functional and structural insights into the transmembrane domain behavior in different membrane environments, the ectodomain bouncing movement, and the dimerization patterns of the intracellular Toll/Interleukin-1 receptor domain. Our work provides TLR4 models as reasonable 3D structures for the (TLR4/MD-2/LPS) architecture accounting for the active (agonist) state of the TLR4, and pointing to a signal transduction mechanism across cell membrane. These observations unveil relevant molecular aspects involved in the TLR4 innate immune pathways and will promote the discovery of new TLR4 modulators.
Toll 样受体 4（TLR4）/髓样分化因子 2（MD-2）先天免疫系统是一个至关重要的膜受体，作为治疗靶点。其组装，在结合革兰氏阴性菌脂多糖（LPS）后，也依赖于膜组成，最终引发免疫反应级联。我们结合从头计算、分子对接、全原子分子动力学模拟和热力学计算，提供了迄今为止最真实和完整的嵌入真实膜中的活性全长 TLR4 复合物的 3D 模型。我们的研究提供了功能和结构上的见解，了解跨不同膜环境的跨膜结构域行为、胞外结构域反弹运动以及细胞内 Toll/白细胞介素-1 受体结构域的二聚化模式。我们的工作提供了 TLR4 模型，作为（TLR4/MD-2/LPS）结构的合理 3D 结构，考虑了 TLR4 的活性（激动剂）状态，并指出了跨细胞膜的信号转导机制。这些观察结果揭示了 TLR4 先天免疫途径中涉及的相关分子方面，并将促进新的 TLR4 调节剂的发现。
