title: TLR4/MD-2 activation by a synthetic agonist with no similarity to LPS.
abstract: 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.
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Lijing
authors.initials: L
authors.lastname: Su
authors.affiliation: Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Morin
authors.affiliation: Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Brian T
authors.initials: BT
authors.lastname: Jones
authors.affiliation: Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Landon R
authors.initials: LR
authors.lastname: Whitby
authors.affiliation: Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Murali M R P
authors.initials: MM
authors.lastname: Surakattula
authors.affiliation: Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037.
authors.forename: Hua
authors.initials: H
authors.lastname: Huang
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Hexin
authors.initials: H
authors.lastname: Shi
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Jin Huk
authors.initials: JH
authors.lastname: Choi
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Kuan-wen
authors.initials: KW
authors.lastname: Wang
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Eva Marie Y
authors.initials: EM
authors.lastname: Moresco
authors.affiliation: Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037.
authors.forename: Michael
authors.initials: M
authors.lastname: Berger
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Zhan
authors.affiliation: Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390; Bruce.Beutler@UTSouthwestern.edu boger@scripps.edu zhang@chop.swmed.edu.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037; Bruce.Beutler@UTSouthwestern.edu boger@scripps.edu zhang@chop.swmed.edu.
authors.forename: Dale L
authors.initials: DL
authors.lastname: Boger
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390; Bruce.Beutler@UTSouthwestern.edu boger@scripps.edu zhang@chop.swmed.edu.
authors.forename: Bruce
authors.initials: B
authors.lastname: Beutler
mesh_terms: D000818:Animals; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051218:Lymphocyte Antigen 96 / Q000819:agonists*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D057786:Peptidomimetics / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000819:agonists*
chemical_list: D008070:Lipopolysaccharides; C411728:Ly96 protein, mouse; D051218:Lymphocyte Antigen 96; D016328:NF-kappa B; D057786:Peptidomimetics; D051197:Toll-Like Receptor 4; C498588:Tbk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases
keywords: crystal structure; innate immunity; neoseptins; peptidomimetic compounds; proinflammatory response
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