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A modulator-bound GPCR structure enables allosteric non-opioid analgesia

Structural studies of a positive allosteric modulator of the adenosine A1 receptor demonstrate the mechanisms by which stabilization of the GPCR–G protein complex bound to its endogenous agonist yields analgesic efficacy in an animal model of neuropathic pain.

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Fig. 1: Allosteric modulation of the A1R promotes agonist–A1R–PAM–G protein complex stability and analgesia in a disease-state-specific manner.


  1. Vos, T. et al. Lancet 388, 1545–1602 (2016).

    Article  Google Scholar 

  2. Volkow, N. D. & McLellan, A. T. N. Engl. J. Med. 374, 1253–1263 (2016).

    Article  CAS  Google Scholar 

  3. Draper-Joyce, C. J. et al. Nature 597, 571–576 (2021).

    Article  CAS  Google Scholar 

  4. Santos, R. et al. Nat. Rev. Drug Discov. 16, 19–34 (2017).

    Article  CAS  Google Scholar 

  5. Shoichet, B. K. & Kobilka, B. K. Trends Pharmacol. Sci. 33, 268–272 (2012).

    Article  CAS  Google Scholar 

  6. Manglik, A. et al. Nature 537, 185–190 (2016).

    Article  CAS  Google Scholar 

  7. Zylka, M. J. Trends Mol. Med. 17, 188–196 (2011).

    Article  CAS  Google Scholar 

  8. Sosnowski, M., Stevens, C. W. & Yaksh, T. L. J. Pharmacol. Exp. Ther. 250, 915–922 (1989).

    CAS  PubMed  Google Scholar 

  9. Li, J. & Perl, E. R. J. Neurophysiol. 72, 1611–1621 (1994).

    Article  CAS  Google Scholar 

  10. Headrick, J. P., Ashton, K. J., Rose’meyer, R. B. & Peart, J. N. Pharmacol. Ther. 140, 92–111 (2013).

    Article  CAS  Google Scholar 

  11. Thal, D. M., Glukhova, A., Sexton, P. M. & Christopoulos, A. Nature 559, 45–53 (2018).

    Article  CAS  Google Scholar 

  12. Sawynok, J. Handb. Exp. Pharmacol. 309–328 (2007).

  13. Aurelio, L. et al. J. Med. Chem. 52, 4543–4547 (2009).

    Article  CAS  Google Scholar 

  14. Sharma, N. et al. Nature 577, 392–398 (2020).

    Article  CAS  Google Scholar 

  15. Usoskin, D. et al. Nat. Neurosci. 18, 145–153 (2015).

    Article  CAS  Google Scholar 

  16. Renthal, W. et al. Neuron 108, 128–144.e9 (2020).

    Article  CAS  Google Scholar 

  17. Araldi, D., Ferrari, L. F. & Levine, J. D. Pain 157, 698–709 (2016).

    Article  CAS  Google Scholar 

  18. Corder, G. et al. Nat. Med. 23, 164–173 (2017).

    Article  CAS  Google Scholar 

  19. Basbaum, A. I., Bautista, D. M., Scherrer, G. & Julius, D. Cell 139, 267–284 (2009).

    Article  CAS  Google Scholar 

  20. Yudin, Y. & Rohacs, T. Mol. Pain 14, 1744806918763646 (2018).

    Article  CAS  Google Scholar 

  21. Avlani, V. A. et al. J. Biol. Chem. 282, 25677–25686 (2007).

    Article  CAS  Google Scholar 

  22. Cao, A.-M. et al. Nat. Commun. 12, 5426 (2021).

    Article  CAS  Google Scholar 

  23. Kandasamy, R. et al. Proc. Natl. Acad. Sci. USA 118, e2000017118 (2021).

    Article  CAS  Google Scholar 

  24. Che, T. & Roth, B. L. Annu. Rev. Biochem. 90, 739–761 (2021).

    Article  CAS  Google Scholar 

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G.S. is a New York Stem Cell Foundation – Robertson Investigator. We thank Joshua Blair for editing the manuscript.

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Correspondence to Grégory Scherrer.

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Lee, D.F., Geron, M. & Scherrer, G. A modulator-bound GPCR structure enables allosteric non-opioid analgesia. Nat Struct Mol Biol 28, 871–872 (2021).

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