5ijb
From Proteopedia
The ligand-free structure of the mouse TLR4/MD-2 complex
Structural highlights
Disease[TLR4_MOUSE] Note=The protein is encoded by the Lps locus, an important susceptibility locus, influencing the propensity to develop a disseminated Gram-negative infection. Function[TLR4_MOUSE] Cooperates with LY96 and CD14 to mediate the innate immune response to bacterial lipopolysaccharide (LPS). Acts via MYD88, TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (By similarity).[1] [LY96_MOUSE] Cooperates with TLR4 in the innate immune response to bacterial lipopolysaccharide (LPS), and with TLR2 in the response to cell wall components from Gram-positive and Gram-negative bacteria. Enhances TLR4-dependent activation of NF-kappa-B. Cells expressing both MD2 and TLR4, but not TLR4 alone, respond to LPS (By similarity). Publication Abstract from PubMedStructurally 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-A 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. TLR4/MD-2 activation by a synthetic agonist with no similarity to LPS.,Wang Y, Su L, Morin MD, Jones BT, Whitby LR, Surakattula MM, Huang H, Shi H, Choi JH, Wang KW, Moresco EM, Berger M, Zhan X, Zhang H, Boger DL, Beutler B Proc Natl Acad Sci U S A. 2016 Feb 16;113(7):E884-93. doi:, 10.1073/pnas.1525639113. Epub 2016 Feb 1. PMID:26831104[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Berger, M | Beutler, B | Boger, D L | Choi, J H | Huang, H | Jones, B T | Moresco, E M | Morin, M D | Shi, H | Su, L | Surakattula, M | Wang, K | Wang, Y | Whitby, L R | Zhan, X | Zhang, H | Immune system | Leucine-rich repeat
