The Structural Basis for Endotoxin-induced Allosteric Regulation of the Toll-like Receptor 4 (TLR4) Innate Immune Receptor

摘要: As part of the innate immune system, Toll-like receptor 4 (TLR4) recognizes bacterial cell surface lipopolysaccharide (LPS) by forming a complex with lipid-binding co-receptor, MD-2. In presence agonist, TLR4·MD-2 dimerizes to form an active complex, leading initiation intracellular inflammatory signals. TLR4 is great biomedical interest, but its pharmacological manipulation complicated because even subtle variations in structure LPS can profoundly impact resultant immunological response. Here, we use atomically detailed molecular simulations gain insights into nature signaling mechanism. We first demonstrate that MD-2 extraordinarily flexible. The "clamshell-like" motions β-cup fold enable it sensitively match volume hydrophobic cavity size and shape bound lipid moiety. show allosterically transmits this conformational plasticity, ligand-dependent manner, phenylalanine residue (Phe-126) at mouth previously implicated activation. Remarkably, within observe spontaneous transitions between inactive states Phe-126, confirm Phe-126 indeed "molecular switch" endotoxic signaling.