de Aguiar Carla, Costa Mauricio G S, Verli Hugo
Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul, Av. Bento Gonçalves 9500, CP 15005, Porto Alegre, 91500-970, RS, Brazil.
Proteins. 2015 Feb;83(2):373-82. doi: 10.1002/prot.24739.
The interaction between human Toll-like receptor 4 (hTLR4) and its coreceptor, myeloid differentiation factor 2 (MD-2), is important in Gram-negative bacteria lipopolysaccharide (LPS) recognition. In this process, MD-2 recognizes LPS and promotes the dimerization of the complex hTLR4-MD-2-LPS, triggering an intracellular immune signaling. In this study, we employed distinct computational methods to explore the dynamical properties of the hTLR4-MD-2 complex and investigated the implications of the coreceptor complexation to the structural biology of hTLR4. We characterized both global and local dynamics of free and MD-2 complexed hTLR4, in both (hTLR4-MD-2)1 and (hTLR4-MD-2)2 states. Both molecular dynamics and normal mode analysis reveled a stabilization of the terminal regions of hTLR4 upon complexation to MD-2. We are able to identify conserved important residues involved on the hTLR4-MD-2 interaction dynamics and disclose C-terminal motions that may be associated to the signaling process upon oligomerization.
人类Toll样受体4（hTLR4）与其共受体髓样分化因子2（MD-2）之间的相互作用在革兰氏阴性菌脂多糖（LPS）识别中至关重要。在此过程中，MD-2识别LPS并促进hTLR4-MD-2-LPS复合物的二聚化，触发细胞内免疫信号传导。在本研究中，我们采用不同的计算方法来探索hTLR4-MD-2复合物的动力学特性，并研究共受体复合对hTLR4结构生物学的影响。我们表征了游离的和与MD-2复合的hTLR4在（hTLR4-MD-2）1和（hTLR4-MD-2）2状态下的全局和局部动力学。分子动力学和正常模式分析均显示，与MD-2复合后hTLR4末端区域得到稳定。我们能够识别参与hTLR4-MD-2相互作用动力学的保守重要残基，并揭示可能与寡聚化后信号传导过程相关的C末端运动。
