دورية أكاديمية
TLR4/MD-2 activation by a synthetic agonist with no similarity to LPS.
| العنوان: | TLR4/MD-2 activation by a synthetic agonist with no similarity to LPS. |
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| المؤلفون: | Wang Y; Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390;, Su L; Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390;, Morin MD; Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037;, Jones BT; Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037;, Whitby LR; Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037;, Surakattula MM; Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037;, Huang H; Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037., Shi H; Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390;, Choi JH; Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390;, Wang KW; Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390;, Moresco EM; Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390;, Berger M; Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037., Zhan X; Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390;, Zhang H; Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390; Bruce.Beutler@UTSouthwestern.edu boger@scripps.edu zhang@chop.swmed.edu., Boger DL; Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037; Bruce.Beutler@UTSouthwestern.edu boger@scripps.edu zhang@chop.swmed.edu., Beutler B; 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. |
| المصدر: | Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2016 Feb 16; Vol. 113 (7), pp. E884-93. Date of Electronic Publication: 2016 Feb 01. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S. |
| اللغة: | English |
| بيانات الدورية: | Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, DC : National Academy of Sciences |
| مواضيع طبية MeSH: | Lipopolysaccharides/*pharmacology , Lymphocyte Antigen 96/*agonists , Peptidomimetics/*pharmacology , Toll-Like Receptor 4/*agonists, Animals ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mitogen-Activated Protein Kinases/metabolism ; NF-kappa B/metabolism ; Protein Serine-Threonine Kinases/metabolism ; Signal Transduction |
| مستخلص: | 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. |
| التعليقات: | Erratum in: Proc Natl Acad Sci U S A. 2016 Apr 5;113(14 ):E2096. (PMID: 27036010) Erratum in: Proc Natl Acad Sci U S A. 2021 Jun 15;118(24):. (PMID: 34099570) |
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| معلومات مُعتمدة: | R01 GM104496 United States GM NIGMS NIH HHS; U19 AI100627 United States AI NIAID NIH HHS; U24 AI082657 United States AI NIAID NIH HHS; R01GM104496 United States GM NIGMS NIH HHS |
| فهرسة مساهمة: | Keywords: crystal structure; innate immunity; neoseptins; peptidomimetic compounds; proinflammatory response |
| سلسلة جزيئية: | PDB 5HG3; 5HG4; 5HG6 |
| المشرفين على المادة: | 0 (Lipopolysaccharides) 0 (Ly96 protein, mouse) 0 (Lymphocyte Antigen 96) 0 (NF-kappa B) 0 (Peptidomimetics) 0 (Toll-Like Receptor 4) EC 2.7.1.- (Tbk1 protein, mouse) EC 2.7.11.1 (Protein Serine-Threonine Kinases) EC 2.7.11.24 (Mitogen-Activated Protein Kinases) |
| تواريخ الأحداث: | Date Created: 20160203 Date Completed: 20160803 Latest Revision: 20211203 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC4763747 |
| DOI: | 10.1073/pnas.1525639113 |
| PMID: | 26831104 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1091-6490 |
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| DOI: | 10.1073/pnas.1525639113 |