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

Ying Wang; Lijing Su; Matthew D. Morin; Brian T. Jones; Landon R. Whitby; Murali M.R.P. Surakattula; Hua Huang; Hexin Shi; Jin Huk Choi; Kuan Wen Wang; Eva Marie Y. Moresco; Michael Berger; Xiaoming Zhan; Hong Zhang; Dale L. Boger; Bruce Beutler

doi:10.1073/pnas.1525639113

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

Ying Wang, Lijing Su, Matthew D. Morin, Brian T. Jones, Landon R. Whitby, Murali M.R.P. Surakattula, Hua Huang, Hexin Shi, Jin Huk Choi, Kuan Wen Wang, Eva Marie Y. Moresco, Michael Berger, Xiaoming Zhan, Hong Zhang, Dale L. Boger, Bruce Beutler

Department of Immunology and Cancer Research

The Hebrew University of Jerusalem

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	E884-E893
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	113
Issue number	7
DOIs	https://doi.org/10.1073/pnas.1525639113
State	Published - 16 Feb 2016

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Crystal structure
Innate immunity
Neoseptins
Peptidomimetic compounds
Proinflammatory response

All Science Journal Classification (ASJC) codes

General

Access to Document

10.1073/pnas.1525639113

Cite this

Wang, Y., Su, L., Morin, M. D., Jones, B. T., Whitby, L. R., Surakattula, M. M. R. P., Huang, H., Shi, H., Choi, J. H., Wang, K. W., Moresco, E. M. Y., Berger, M., Zhan, X., Zhang, H., Boger, D. L., & Beutler, B. (2016). 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, 113(7), E884-E893. https://doi.org/10.1073/pnas.1525639113

@article{a2ab0f97b69e418b8225fc50053811b7,

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-{\AA} 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.",

keywords = "Crystal structure, Innate immunity, Neoseptins, Peptidomimetic compounds, Proinflammatory response",

author = "Ying Wang and Lijing Su and Morin, \{Matthew D.\} and Jones, \{Brian T.\} and Whitby, \{Landon R.\} and Surakattula, \{Murali M.R.P.\} and Hua Huang and Hexin Shi and Choi, \{Jin Huk\} and Wang, \{Kuan Wen\} and Moresco, \{Eva Marie Y.\} and Michael Berger and Xiaoming Zhan and Hong Zhang and Boger, \{Dale L.\} and Bruce Beutler",

note = "Funding Information: We thank Ian Wilson for the initial design of the mouse TLR4VLR and MD2-protein A hybrid constructs for coexpression of the complex; Jose Rizo-Rey for help with the NMR experiments; Diana Tomchick and Srinivasan Raghunathan for help with X-ray data collection and structure determination; and Peter Jurek and Anne Murray for assistance with manuscript preparation. Results shown in this report are derived from work performed at Argonne National Laboratory, Structural Biology Center at Advanced Photon Source. Argonne is operated by UChicago Argonne, LLC, for the US Department of Energy, Office of Biological and Environmental Research under Contract DE-AC02-06CH11357. This work was supported by NIH/National Institute of General Medical Sciences (NIGMS) Grant R01GM104496 (to H.Z.) and NIH/National Institute of Allergy and Infectious Diseases (NIAID) Grants U24 AI082657 (to B.B. and D.L.B.) and U19 AI100627 (to B.B.).",

year = "2016",

month = feb,

day = "16",

doi = "10.1073/pnas.1525639113",

language = "الإنجليزيّة",

volume = "113",

pages = "E884--E893",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

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Wang, Y, Su, L, Morin, MD, Jones, BT, Whitby, LR, Surakattula, MMRP, Huang, H, Shi, H, Choi, JH, Wang, KW, Moresco, EMY, Berger, M, Zhan, X, Zhang, H, Boger, DL & Beutler, B 2016, '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, vol. 113, no. 7, pp. E884-E893. https://doi.org/10.1073/pnas.1525639113

TY - JOUR

T1 - TLR4/MD-2 activation by a synthetic agonist with no similarity to LPS

AU - Wang, Ying

AU - Su, Lijing

AU - Morin, Matthew D.

AU - Jones, Brian T.

AU - Whitby, Landon R.

AU - Surakattula, Murali M.R.P.

AU - Huang, Hua

AU - Shi, Hexin

AU - Choi, Jin Huk

AU - Wang, Kuan Wen

AU - Moresco, Eva Marie Y.

AU - Berger, Michael

AU - Zhan, Xiaoming

AU - Zhang, Hong

AU - Boger, Dale L.

AU - Beutler, Bruce

N1 - Funding Information: We thank Ian Wilson for the initial design of the mouse TLR4VLR and MD2-protein A hybrid constructs for coexpression of the complex; Jose Rizo-Rey for help with the NMR experiments; Diana Tomchick and Srinivasan Raghunathan for help with X-ray data collection and structure determination; and Peter Jurek and Anne Murray for assistance with manuscript preparation. Results shown in this report are derived from work performed at Argonne National Laboratory, Structural Biology Center at Advanced Photon Source. Argonne is operated by UChicago Argonne, LLC, for the US Department of Energy, Office of Biological and Environmental Research under Contract DE-AC02-06CH11357. This work was supported by NIH/National Institute of General Medical Sciences (NIGMS) Grant R01GM104496 (to H.Z.) and NIH/National Institute of Allergy and Infectious Diseases (NIAID) Grants U24 AI082657 (to B.B. and D.L.B.) and U19 AI100627 (to B.B.).

PY - 2016/2/16

Y1 - 2016/2/16

N2 - 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.

AB - 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.

KW - Crystal structure

KW - Innate immunity

KW - Neoseptins

KW - Peptidomimetic compounds

KW - Proinflammatory response

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U2 - 10.1073/pnas.1525639113

DO - 10.1073/pnas.1525639113

M3 - مقالة

C2 - 26831104

SN - 0027-8424

VL - 113

SP - E884-E893

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 7

ER -

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

Abstract

UN SDGs

Keywords

All Science Journal Classification (ASJC) codes

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