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Found 3 records.
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1. (CSDB ID: 26178) | report error |
| 3HOMyr-(1-2)-+ | Myr-(1-3)-3HOMyr-(1-3)-+ | | | Lau-(1-3)-3HOMyr-(1-2)-b-D-Glcp-(1-6)-a-D-Glcp-(1-P | | P-4)-+ | | 3HOMyr-(1-3)-+ | Show graphically |
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Escherichia coli
(NCBI TaxID 562,
species name lookup)
]
wustl.edu>; R.J. Woods <rwoodsccrc.uga.edu>The human immune response to an infection by Gram-negative bacteria involves detection of lipopolysaccharides (LPS), also known as endotoxins, which comprise the bacterial outer cell wall. Distinct from mammalian glycolipid structures, LPS have a conserved chemical pattern that is recognized by the pattern recognition receptor complex formed by myeloid differentiation protein 2 (MD-2) and toll-like receptor 4 (TLR4). A remarkable immune-mediated structure-toxicity relationship has been defined that relates to the number of acyl chains in the endotoxin. While there is a clear correlation between endotoxin acylation and elicited agonist or antagonist responses, the 3D structural basis of this relationship remains unclear. In order to explore, at atomic-resolution, the effects of a range of chemically distinct endotoxins on the structure and dynamics of their MD-2.endotoxin complexes, we examined a series of variably acylated lipid A molecules from Escherichia coli and Neisseria meningitidis in complex with human MD-2. Through the application of molecular dynamics simulations, in concert with experimental data, we have identified specific structural and dynamic features of the MD-2-endotoxin complexes that may control dimerization of TLR4 molecules. As dimerization is central to the release of downstream chemical mediators, the results provide a structural foundation for the ability of endotoxins to act as either agonists or antagonists of the TLR4 pathway.
Lipopolysaccharide, lipid A, endotoxin, TLR4, molecular dynamics simulations, MD-2
Structure type: oligomer|
2. (CSDB ID: 27159) | report error |
| R-3HOMyr-(1-2)-+ | Myr-(1-3)-R-3HOMyr-(1-3)-+ | | | Lau-(1-3)-R-3HOMyr-(1-2)-b-D-GlcpN-(1-6)-a-D-GlcpN-(1-P | | P-4)-+ | | R-3HOMyr-(1-3)-+ | Show graphically |
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Escherichia coli
(NCBI TaxID 562,
species name lookup)
]boku.ac.atMolecular dynamics simulations of Lipid A and its natural precursor Lipid IVA from E.coli have been carried out free in solution, bound to the myeliod differentiation protein 2 (MD2) and in the complex of MD2 with the toll like receptor 4 (TLR4). In addition, simulations of the ligand free MD2 and MD2-TLR4 complex were performed. A structural and energetic characterization of the bound and unbound states of Lipid A/IVA was generated. As the crystal structures depict, the main driving force for MD2-Lipid A/IVA are the hydrophobic interactions between the aliphatic tails and the MD2 cavity. The charged phosphate groups do strongly interact with positively charged residues, located at the surface of MD2. However, they are not essential for keeping the lipids in the cavity, indicating a more prominent role in binding recognition and ionic interactions with TLR4 at the MD2/TLR4 interface. Interestingly, in the absence of any ligand MD2 rapidly closes, blocking the binding cavity. The presence of TLR4, though changing the dynamics, was not able to impede the aforementioned closing event. We hypothesize that fluctuations of the H1 region are essential for this phenomenon, and it is plausible that an equilibrium between the open and closed states exists, although the lengths of our simulations are not sufficient to encompass the reversible process. The MD2/Lipid A-TLR4 complex simulations show that the presence of the ligand energetically stabilizes the complex relative to the ligand-free structures, indicating cooperativity in the binding process.
TLR4, MD2, lipid IVA, free energy
Structure type: oligomer|
3. (CSDB ID: 31980) | report error |
| Lau-(1-3)-R-3HOMyr-(1-2)-+ | R-3HOLau-(1-3)-+ | | | Lau-(1-3)-R-3HOMyr-(1-2)-b-D-GlcpN-(1-6)-a-D-GlcpN-(1-P | | P-4)-+ | | R-3HOLau-(1-3)-+ | Show graphically |
|
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Neisseria meningitidis
(NCBI TaxID 487,
species name lookup)
]wustl.edu>; R.J. Woods <rwoodsccrc.uga.edu>The human immune response to an infection by Gram-negative bacteria involves detection of lipopolysaccharides (LPS), also known as endotoxins, which comprise the bacterial outer cell wall. Distinct from mammalian glycolipid structures, LPS have a conserved chemical pattern that is recognized by the pattern recognition receptor complex formed by myeloid differentiation protein 2 (MD-2) and toll-like receptor 4 (TLR4). A remarkable immune-mediated structure-toxicity relationship has been defined that relates to the number of acyl chains in the endotoxin. While there is a clear correlation between endotoxin acylation and elicited agonist or antagonist responses, the 3D structural basis of this relationship remains unclear. In order to explore, at atomic-resolution, the effects of a range of chemically distinct endotoxins on the structure and dynamics of their MD-2.endotoxin complexes, we examined a series of variably acylated lipid A molecules from Escherichia coli and Neisseria meningitidis in complex with human MD-2. Through the application of molecular dynamics simulations, in concert with experimental data, we have identified specific structural and dynamic features of the MD-2-endotoxin complexes that may control dimerization of TLR4 molecules. As dimerization is central to the release of downstream chemical mediators, the results provide a structural foundation for the ability of endotoxins to act as either agonists or antagonists of the TLR4 pathway.
Lipopolysaccharide, lipid A, endotoxin, TLR4, molecular dynamics simulations, MD-2
Structure type: oligomer| New query | Export IDs | Home | Help |
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