The vast majority of available structures have been deposited in the Protein Data Bank (PDB) in the past decade (Supplementary Table ). However, almost all are single domains of TLRs. Obtaining full-length structures of TLRs remains a challenge. So far, only the LRR and TM domains of TLR3 and TLR7 have been determined together as a result of the Cryo-EM experiment . Furthermore, there is a large disproportion in the number of structures between the individual members of the TLRs family. The biggest number of structures has been deposited for the LRR domain of TLR8. In contrast, other TLRs have very few (or none) representative structures of their particular domains. Investigation of the available structures revealed that a part of them miss a number of residues, which worsens their overall quality. Moreover, some deposited LRR domains of TLR1, TLR2, and TLR4 are hybrids of human TLR with hagfish variable lymphocyte receptor B. Those factors make not only the structural analysis but also studies on ligand binding, receptor activation, signal transduction and modulator design not trivial. An interesting combination of computational and experimental approaches was applied for the identification and understanding of the Zn binding to the TIR domain . Lushpa et al.