title: The structural basis for endotoxin-induced allosteric regulation of the Toll-like receptor 4 (TLR4) innate immune receptor.
abstract: As part of the innate immune system, Toll-like receptor 4 (TLR4) recognizes bacterial cell surface lipopolysaccharide (LPS) by forming a complex with a lipid-binding co-receptor, MD-2. In the presence of agonist, TLR4·MD-2 dimerizes to form an active receptor complex, leading to initiation of intracellular inflammatory signals. TLR4 is of great biomedical interest, but its pharmacological manipulation is complicated because even subtle variations in the structure of LPS can profoundly impact the resultant immunological response. Here, we use atomically detailed molecular simulations to gain insights into the nature of the molecular signaling mechanism. We first demonstrate that MD-2 is extraordinarily flexible. The "clamshell-like" motions of its β-cup fold enable it to sensitively match the volume of its hydrophobic cavity to the size and shape of the bound lipid moiety. We show that MD-2 allosterically transmits this conformational plasticity, in a ligand-dependent manner, to a phenylalanine residue (Phe-126) at the cavity mouth previously implicated in TLR4 activation. Remarkably, within the receptor complex, we observe spontaneous transitions between active and inactive signaling states of Phe-126, and we confirm that Phe-126 is indeed the "molecular switch" in endotoxic signaling.
authors.affiliation: From the Unilever Centre for Molecular Science Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom.
authors.forename: Teresa
authors.initials: T
authors.lastname: Paramo
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Piggot
authors.forename: Clare E
authors.initials: CE
authors.lastname: Bryant
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Bond
mesh_terms: D000494:Allosteric Regulation; D000495:Allosteric Site; D006801:Humans; D008055:Lipids / Q000737:chemistry; D008070:Lipopolysaccharides / Q000737:chemistry* / Q000494:pharmacology; D051218:Lymphocyte Antigen 96 / Q000737:chemistry / Q000378:metabolism; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D051197:Toll-Like Receptor 4 / Q000737:chemistry* / Q000378:metabolism
chemical_list: D008055:Lipids; D008070:Lipopolysaccharides; D051218:Lymphocyte Antigen 96; D051197:Toll-Like Receptor 4
keywords: Allosteric Regulation; Endotoxin; Hydrophobic Collapse; Lipid A; Lipopolysaccharide (LPS); Molecular Dynamics; Myeloid Differentiation Factor 2 (MD-2); Toll-like receptors (TLRs)