[go: up one dir, main page]
More Web Proxy on the site http://driver.im/
Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Brief Communication
  • Published:

MCC950 closes the active conformation of NLRP3 to an inactive state

Nature Chemical Biology volume 15, pages 560–564 (2019)Cite this article

Subjects

Abstract

NLRP3 (NOD-like receptor pyrin domain-containing protein 3) is an innate immune sensor that contributes to the development of different diseases, including monogenic autoinflammatory syndromes, gout, atherosclerosis, and Alzheimer’s disease. The molecule sulfonylurea MCC950 is a NLRP3 inflammasome inhibitor with potential clinical utility. However, the mechanism of action of MCC950 remains unknown. Here, we characterize the mechanism of action of MCC950 in both wild-type and autoinflammatory-related NLRP3 mutants, and demonstrate that MCC950 closes the ‘open’ conformation of active NLRP3.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: MCC950 closes the conformation of autoinflammatory-associated gain-of-function NLRP3.
Fig. 2: MD simulations of MCC950 targeting the NLRP3 NACHT domain and MCC950 action on the NLRP3 triple walker B mutant.
Fig. 3: MCC950 affects NLRP3 conformation upon activation.

Similar content being viewed by others

Data availability

Source data for Figs. 1, 2 and 3 are presented online. Supplementary Figs. 8 and 9 present data for Figs. 1a,f,g and 3a–c,e as dot-plots to shows data distribution. Supplementary Fig. 10 presents uncropped western blots presented in the main and supplementary figures. All other data supporting the findings of this study are available from the corresponding author upon reasonable request.

References

  1. McGettrick, A. F. et al. Diabetes, Obes. Metab. 15, 19–25 (2013).

    Article  CAS  Google Scholar 

  2. Heneka, M. T. et al. Nat. Immunol. 16, 229–236 (2015).

    Article  CAS  Google Scholar 

  3. Martinon, F. et al. Nature 440, 237–241 (2006).

    Article  CAS  Google Scholar 

  4. Masters, S. L. et al. Sci. Transl. Med. 3, 81ps17 (2011).

    Article  Google Scholar 

  5. de Torre-Minguela, C. et al. Front. Immunol. 8, 43 (2017).

    PubMed  PubMed Central  Google Scholar 

  6. Schroder, K. & Tschopp, J. Cell 140, 821–832 (2010).

    Article  CAS  Google Scholar 

  7. Rubartelli, A. et al. Front. Immunol. 4, 398 (2013).

    Article  Google Scholar 

  8. Hafner-Bratkovič, I. & Pelegrín, P. Curr. Opin. Immunol. 52, 8–17 (2018).

    Article  Google Scholar 

  9. Boucher, D. et al. J. Exp. Med. 215, 827–840 (2018).

    Article  CAS  Google Scholar 

  10. Laliberte, R. E. et al. J. Biol. Chem. 278, 16567–16578 (2003).

    Article  CAS  Google Scholar 

  11. Coll, R. C. et al. Nat. Med. 21, 248–255 (2015).

    Article  CAS  Google Scholar 

  12. Primiano, M. J. et al. J. Immunol. 197, 2421–2433 (2016).

    Article  CAS  Google Scholar 

  13. Jiang, H. et al. J. Exp. Med. 214, 3219–3238 (2017).

    Article  CAS  Google Scholar 

  14. Cocco, M. et al. J. Med. Chem. 60, 3656–3671 (2017).

    Article  CAS  Google Scholar 

  15. Baldwin, A. G. et al. Cell Chem. Biol. 24, 1321–1335.e5 (2017).

    Article  CAS  Google Scholar 

  16. Compan, V. et al. Immunity 37, 487–500 (2012).

    Article  CAS  Google Scholar 

  17. Martín-Sánchez, F. et al. Methods Mol. Biol. 1417, 159–168 (2016).

    Article  Google Scholar 

  18. Mensa-Vilaro, A. et al. Arthritis Rheumatol. 68, 3035–3041 (2016).

    Article  CAS  Google Scholar 

  19. Duncan, J. A. et al. Proc. Natl Acad. Sci. 104, 8041–8046 (2007).

    Article  CAS  Google Scholar 

  20. Hafner-Bratkovič, I. et al. Nat. Commun. 9, 5182 (2018).

    Article  Google Scholar 

  21. He, Y. et al. Nature 530, 354–357 (2016).

    Article  CAS  Google Scholar 

  22. Shi, H. et al. Nat. Immunol. 17, 250–258 (2016).

    Article  CAS  Google Scholar 

  23. Coll, R. C. et al. Nat Chem Biol. https://doi.org/10.1038/s41589-019-0277-7 (2019).

  24. Virginio, C. et al. J. Physiol. 519, 335–346 (1999).

    Article  CAS  Google Scholar 

  25. Martín-Sánchez, F. et al. Cell Death Differ. 23, 1219–1231 (2016).

    Article  Google Scholar 

  26. Compan, V. et al. J. Immunol. 194, 1261–1273 (2015).

    Article  CAS  Google Scholar 

  27. Martín-Sánchez, F. et al. Cell Death Dis 8, e2984 (2017).

    Article  Google Scholar 

  28. Sester, D. P. et al. J. Immunol. 194, 455–462 (2014).

    Article  Google Scholar 

  29. de Torre-Minguela, C. et al. Sci. Rep. 6, 22586 (2016).

    Article  Google Scholar 

  30. Young, M. T. et al. Br. J. Pharmacol. 149, 261–268 (2006).

    Article  CAS  Google Scholar 

  31. Trott, O. & Olson, A. J. Comput. Chem. 31, 455–461 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Frisch, M. J. et al. Gaussian, Inc. (Wallingford, CT, 2016).

  33. Sánchez-Linares, I. et al. BMC Bioinformatics 13, S13 (2012).

    Article  Google Scholar 

Download references

Acknowledgements

We thank M. C. Baños and A. I. Gómez for technical assistance with molecular biology and cell culture. We also wish to thank L. Martínez-Alarcón for help with healthy volunteer blood collection, I. Hafner-Bratkovič (National Institute of Chemistry, Ljubljana, Slovenia) for stable immortalized macrophages lines, and C. Vargas (Hospital Virgen de la Macarena, Sevilla, Spain), E. Ramos and S. Jimenez-Treviño (Hospital Central de Asturias, Oviedo, Spain), and M. Basagaña Torrento (Hospital Universitario Germans Trias i Pujol, Badalona, Spain) for samples from individuals with autoinflammatory syndromes. We also thank the patients and healthy volunteers enrolled in this study, and the Biobanco en Red de la Región de Murcia (PT13/0010/0018), which is integrated into the Spanish National Biobanks Network (B.000859), for its collaboration. This research was partially supported by the e-infrastructure program of the Research Council of Norway, and the supercomputer center of UiT at the Arctic University of Norway. The authors are also grateful for the computer resources at CTE-POWER and the technical support provided by Barcelona Supercomputing Center (RES-BCV-2018-3-0008). H.M.-B. was supported by a Rio Hortega fellowship from the Instituto Salud Carlos III (CM14/00008). D.A.-B. was supported by a Juan de la Cierva postdoctoral fellowship from the Ministerio de Economía y Competitividad (FJCI-2014-22041). This work was supported by grants from the Instituto Salud Carlos III-Fondo Europeo de Desarrollo Regional (PI13/00174 to P.P.), the Ministerio de Economia, Industria y Competitividad–Fondo Europeo de Desarrollo Regional (project nos. SAF2017-88276-R to P.P. and CTQ2017-87974-R to H.P.-S.), Fundación Séneca (20859/PI/18 to P.P.), and the European Research Council (ERC-2013-CoG 614578 to P.P.).

Author information

Authors and Affiliations

  1. Biomedical Research Institute of Murcia (IMIB-Arrixaca), University Clinical Hospital Virgen de la Arrixaca, Murcia, Spain

    Ana Tapia-Abellán, Diego Angosto-Bazarra, Helios Martínez-Banaclocha, Carlos de Torre-Minguela & Pablo Pelegrin

  2. Bioinformatics and High Performance Computing Research Group (BIO-HPC), Computer Engineering Department, Universidad Católica de Murcia (UCAM), Murcia, Spain

    Jose P. Cerón-Carrasco & Horacio Pérez-Sánchez

  3. Department of Immunology, Hospital Clinic-IDIBAPS, Barcelona, Spain

    Juan I. Arostegui

Authors
  1. Ana Tapia-Abellán
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Diego Angosto-Bazarra
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Helios Martínez-Banaclocha
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Carlos de Torre-Minguela
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jose P. Cerón-Carrasco
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Horacio Pérez-Sánchez
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Juan I. Arostegui
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Pablo Pelegrin
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A.T.-A., D.A.-B., H.M.-B. and C.dT.-M. conducted the experiments and interpreted data. J.P.C.-C. and H.P.-S. conducted BD and MD simulations. D.A.-B. performed structural modeling. J.I.A. coordinated human samples from autoinflammatory individuals. P.P. conceived, designed, and supervised this study, wrote the paper with feedback from all coauthors, and sourced funding.

Corresponding author

Correspondence to Pablo Pelegrin.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary Figures 1–10

Reporting Summary

Source data

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tapia-Abellán, A., Angosto-Bazarra, D., Martínez-Banaclocha, H. et al. MCC950 closes the active conformation of NLRP3 to an inactive state. Nat Chem Biol 15, 560–564 (2019). https://doi.org/10.1038/s41589-019-0278-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41589-019-0278-6

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research