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PDBsum entry 5ijd
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Immune system
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PDB id
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5ijd
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References listed in PDB file
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Key reference
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Title
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Tlr4/md-2 activation by a synthetic agonist with no similarity to lps.
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Authors
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Y.Wang,
L.Su,
M.D.Morin,
B.T.Jones,
L.R.Whitby,
M.M.Surakattula,
H.Huang,
H.Shi,
J.H.Choi,
K.W.Wang,
E.M.Moresco,
M.Berger,
X.Zhan,
H.Zhang,
D.L.Boger,
B.Beutler.
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Ref.
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Proc Natl Acad Sci U S A, 2016,
113,
E884.
[DOI no: ]
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PubMed id
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Abstract
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Structurally disparate molecules reportedly engage and activate Toll-like
receptor (TLR) 4 and other TLRs, yet the interactions that mediate binding and
activation by dissimilar ligands remain unknown. We describe Neoseptins,
chemically synthesized peptidomimetics that bear no structural similarity to the
established TLR4 ligand, lipopolysaccharide (LPS), but productively engage the
mouse TLR4 (mTLR4)/myeloid differentiation factor 2 (MD-2) complex. Neoseptin-3
activates mTLR4/MD-2 independently of CD14 and triggers canonical myeloid
differentiation primary response gene 88 (MyD88)- and Toll-interleukin 1
receptor (TIR) domain-containing adaptor inducing IFN-beta (TRIF)-dependent
signaling. The crystal structure mTLR4/MD-2/Neoseptin-3 at 2.57-Å resolution
reveals that Neoseptin-3 binds as an asymmetrical dimer within the hydrophobic
pocket of MD-2, inducing an active receptor complex similar to that induced by
lipid A. However, Neoseptin-3 and lipid A form dissimilar molecular contacts to
achieve receptor activation; hence strong TLR4/MD-2 agonists need not mimic LPS.
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