Toll-like receptors (TLRs) are the key participants in the innate immune system. Activation of TLRs leads to the development of an immune response and inflammation, the receptors of the family are involved in the development of a number of diseases, including sepsis, immunodeficiency, atherosclerosis, and asthma. Despite the apparent clarity, many unanswered questions remain in the field of the toll-like receptors structural biology. To obtain the necessary data, studies of intracellular (TIR) and transmembrane (TM) domains of TLRs in solution by high-resolution NMR spectroscopy should be considered, as is proposed in the current Project. We propose to do the wide screening of conditions to obtain all TIR domains of TLRs in bacterial cultures in soluble form. This will allow determining the prospects of each of the TIR domains for the further research using NMR spectroscopy and a number of other methods. Then, choosing the most promising TIR domain, it is planned to determine its spatial structure, study its intramolecular mobility, interaction with lipid membranes of various compositions. This will describe the behavior of the domain in the native-environment. Studies of membrane activity will permit to confirm or disprove the hypothesis about the role of the cell membrane in the processes of activation of the toll-like receptors. To study the organization of the TLR juxtamembrane regions, the spatial structures of TM domains with short juxtamembrane segments will be obtained in a different membrane-like environment, for two representatives of the TLR family. Finally, the structure of the N-terminal domain of MyD88, the key intracellular partner of most TLRs will be determined.