Abstract
Toll-like receptor 4 (TLR4), along with its accessory protein myeloid differentiation factor 2 (MD-2), builds a heterodimeric complex that specifically recognizes lipopolysaccharides (LPS), which are present on the cell wall of Gram-negative bacteria, activating the innate immune response. Some TLR4 modulators are undergoing preclinical and clinical evaluation for the treatment of sepsis, inflammatory diseases, cancer and rheumatoid arthritis. Since the relatively recent elucidation of the X-ray crystallographic structure of the extracellular domain of TLR4, research around this fascinating receptor has risen to a new level, and thus, new perspectives have been opened. In particular, diverse computational techniques have been applied to decipher some of the basis at the atomic level regarding the mechanism of functioning and the ligand recognition processes involving the TLR4/MD-2 system at the atomic level. This review summarizes the reported molecular modeling and computational studies that have recently provided insights into the mechanism regulating the activation/inactivation of the TLR4/MD-2 system receptor and the key interactions modulating the molecular recognition process by agonist and antagonist ligands. These studies have contributed to the design and the discovery of novel small molecules with promising activity as TLR4 modulators.
Highlights
Toll-like receptors (TLRs) are pattern recognition receptors with a primordial role in the activation of the innate immunity, and in particular, the Toll-like receptor 4 (TLR4) is the mammalian endotoxin sensor [1]
This review summarizes the reported molecular modeling and computational studies that have recently provided insights into the mechanism regulating the activation/inactivation of the TLR4/myeloid differentiation factor 2 (MD-2) system receptor and the key interactions modulating the molecular recognition process by agonist and antagonist ligands
Among the different TLRs, TLR4 represents an interesting case of study for several reasons: (i) it is the only TLR that needs an accessory protein to become active; (ii) it can activate the immune response through two different signaling pathways; and (iii) when faced with the specific
Summary
Toll-like receptors (TLRs) are pattern recognition receptors with a primordial role in the activation of the innate immunity, and in particular, the Toll-like receptor 4 (TLR4) is the mammalian endotoxin sensor [1]. The immune response mediated by the activation of TLR4 and its co-receptor MD-2 [4] starts with the collection of an LPS by the transport protein cluster of differentiation 14 (CD14), which delivers it MD-2 (Figure 1). The eventual formation of the TLR4/MD-2/TLR4*/MD-2* heterodimer promotes the dimerization of the intracellular domains, which leads to the recruitment of downstream. Adaptors and of of thethe intracellular signaling events and final response. Adaptors and to tothe theactivation activation intracellular signaling events and immune final immune response. The binding of an of antagonist ligand to thetoextracellular domain would prevent the formation of the. The binding an antagonist ligand the extracellular domain would prevent the formation of dimer, and the intracellular signaling events would not occur.
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