TLR4/MD-2 activation by a synthetic agonist with no similarity to LPS.

Proceedings of the National Academy of Sciences of the United States of America
Ying WangBruce Beutler

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.

References

Oct 18, 2000·The Journal of Immunology : Official Journal of the American Association of Immunologists·Q JiangH R Petty
Jan 21, 2001·The Journal of Biological Chemistry·Y OkamuraJ F Strauss
Aug 18, 2001·The Journal of Immunology : Official Journal of the American Association of Immunologists·S T SmileyW W Hancock
Jan 10, 2002·The Journal of Experimental Medicine·Christian TermeerJan Christoph Simon
Feb 14, 2002·The Journal of Biological Chemistry·Ramunas M VabulasHermann Wagner
Mar 26, 2002·The Journal of Biological Chemistry·Ramunas M VabulasHansjorg Schild
May 8, 2002·The Journal of Immunology : Official Journal of the American Association of Immunologists·Geoffrey B JohnsonJeffrey L Platt
May 1, 1997·Acta Crystallographica. Section D, Biological Crystallography·G N MurshudovE J Dodson
Dec 2, 2004·Acta Crystallographica. Section D, Biological Crystallography·Paul Emsley, Kevin Cowtan
Jan 13, 2005·The Journal of Biological Chemistry·Jung-In KimJie-Oh Lee
Mar 26, 2005·Immunological Reviews·Ian R RifkinAnn Marshak-Rothstein
Apr 5, 2005·Acta Crystallographica. Section D, Biological Crystallography·Airlie J McCoyRandy J Read
Jul 19, 2005·The Journal of Clinical Investigation·Liliana SchaeferHermann-Josef Gröne
May 20, 2006·The Journal of Immunology : Official Journal of the American Association of Immunologists·Mieke F RoelofsTimothy R D J Radstake
Jul 21, 2006·Acta Crystallographica. Section D, Biological Crystallography·Wladek MinorMaksymilian Chruszcz
Oct 13, 2006·Journal of Leukocyte Biology·Marco E Bianchi
Dec 12, 2007·Handbook of Experimental Pharmacology·Satoshi Uematsu, Shizuo Akira
Apr 2, 2009·Journal of the American Chemical Society·Alex ShaginianDale L Boger
Jun 19, 2009·The Journal of Immunology : Official Journal of the American Association of Immunologists·Ping ZhangMadeleine W Cunningham
Nov 15, 2011·Cell·Ivan ZanoniJonathan C Kagan
Apr 26, 2012·Proceedings of the National Academy of Sciences of the United States of America·Umeharu OhtoToshiyuki Shimizu
Jul 18, 2012·Accounts of Chemical Research·Landon R Whitby, Dale L Boger
May 10, 2013·Journal of Medicinal Chemistry·Michael ChanHoward B Cottam
Jun 5, 2014·The Journal of Pharmacology and Experimental Therapeutics·Tomoko HayashiDennis A Carson
Jun 25, 2015·Proceedings of the National Academy of Sciences of the United States of America·Rajesh RajaiahStefanie N Vogel

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Citations

Apr 10, 2016·Human Immunology·Philippe Georgel
Jul 9, 2016·Current Opinion in Immunology·Steven G ReedMark T Orr
Jul 1, 2016·Molecular Nutrition & Food Research·Neha M SahasrabudhePaul de Vos
May 20, 2017·Nature Reviews. Neurology·Xi LanJian Wang
Nov 4, 2017·International Journal of Molecular Sciences·Florent Cochet, Francesco Peri
Oct 11, 2017·International Archives of Allergy and Immunology·Geoffrey A Mueller
Jun 13, 2018·Molecular Biology and Evolution·Hana VelováMichal Vinkler
Nov 20, 2018·Medicinal Research Reviews·Muhammad Ayaz AnwarSangdun Choi
Oct 24, 2018·The Journal of Immunology : Official Journal of the American Association of Immunologists·Amit MichaeliAnke Burger-Kentischer
Dec 21, 2018·PLoS Pathogens·Judith OlejnikElke Mühlberger
Feb 7, 2019·PLoS Pathogens·Yidan WangPablo Penaloza-MacMaster
Sep 7, 2019·Inflammation Research : Official Journal of the European Histamine Research Society ... [et Al.]·Ayyanar SivananthamSubbiah Rajasekaran
Dec 26, 2019·Innate Immunity·Jorge Lozano-AponteChristian Alexander
Nov 30, 2019·Biological Chemistry·Sandra Santos-Sierra
Oct 15, 2019·PLoS Computational Biology·Alireza Tafazzol, Yong Duan
May 27, 2020·Acta Pharmacologica Sinica·Simon Van Herck, Bruno G De Geest
Jan 9, 2019·Frontiers in Cellular Neuroscience·Sara BachillerAntonio Boza-Serrano
Nov 16, 2019·Journal of Cardiovascular Pharmacology·Qi-Yang YinYun-Man Li
Sep 26, 2020·Proceedings of the National Academy of Sciences of the United States of America·Van Thai HaMateja Manček-Keber
Apr 8, 2020·Veterinary World·Sianiwati GoenhartoSri Wahjuni
Nov 21, 2020·The Journal of Experimental Medicine·Katharina RichardStefanie N Vogel
Oct 15, 2020·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Natticha SumneangNipon Chattipakorn
Oct 29, 2020·Proceedings of the National Academy of Sciences of the United States of America·Cynthia López-HaberAdriana R Mantegazza
Dec 5, 2020·Biomolecules·Abraham Espinoza-CulupúMonamaris Marques Borges
Feb 13, 2021·Protein Science : a Publication of the Protein Society·Jinta Asami, Toshiyuki Shimizu
Oct 11, 2017·Pharmacology & Therapeutics·Michael J LacagninaPeter M Grace
Apr 6, 2021·Frontiers in Immunology·Holger HeineAlla Zamyatina
Apr 18, 2021·Carbohydrate Research·Cristina Di CarluccioAlba Silipo
Sep 3, 2018·International Journal of Biological Macromolecules·Bahareh VakiliYounes Ghasemi

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