Academic Journal
Προβολή σε EDS

A biased allosteric modulator is a molecular glue for β2AR dimerization.

Λεπτομέρειες βιβλιογραφικής εγγραφής
Τίτλος: A biased allosteric modulator is a molecular glue for β2AR dimerization.
Συγγραφείς: Shen J; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA., Peddada TN; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA., Komolov KE; Department of Biochemistry and Molecular Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA., De Pascali F; Department of Biochemistry and Molecular Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA., Garces AM; Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI, USA., Wang H; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA., Ehsan M; Department of Bionano Engineering, Center for Bionano Intelligence Education and Research, Hanyang University, Ansan, South Korea., Chae PS; Department of Bionano Engineering, Center for Bionano Intelligence Education and Research, Hanyang University, Ansan, South Korea., Lerch MT; Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI, USA., Benovic JL; Department of Biochemistry and Molecular Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA., Xu J; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. xuj8@sustech.edu.cn.; Department of Medical Neuroscience, SUSTech Homeostatic Medicine Institute, School of Medicine, Institute for Biology Electron Microscopy, Southern University of Science and Technology, Shenzhen, China. xuj8@sustech.edu.cn., Kobilka BK; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. kobilka@stanford.edu.
Πηγή: Nature [Nature] 2026 Oct; Vol. 658 (8135), pp. 556-564. Date of Electronic Publication: 2026 Aug 19.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 0410462 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-4687 (Electronic) Linking ISSN: 00280836 NLM ISO Abbreviation: Nature Subsets: MEDLINE
Imprint Name(s): Publication: Basingstoke : Nature Publishing Group
Original Publication: London, Macmillan Journals ltd.
Ιατρικοί όροι (MeSH): Receptors, Adrenergic, beta-2*/chemistry , Receptors, Adrenergic, beta-2*/metabolism , Receptors, Adrenergic, beta-2*/ultrastructure , Protein Multimerization*/drug effects , Cryoelectron Microscopy*, Allosteric Regulation/drug effects ; beta-Arrestins/metabolism ; beta-Arrestins/chemistry ; Signal Transduction/drug effects ; Models, Molecular ; Humans ; Animals ; Ligands ; HEK293 Cells
Περίληψη: Family A G-protein-coupled receptors (GPCRs) are typically described as monomers, yet growing evidence suggests that they can form dimers with distinct signalling properties1-3. However, the mechanisms and therapeutic potential of such dimerization remain poorly understood. Here we show that AP-7-168, an optimized derivative of a β-arrestin-biased negative allosteric modulator of the β2-adrenergic receptor (β2AR) that sustains bronchorelaxation in cell and tissue models4, functions as a molecular glue to stabilize β2AR homodimerization. Cryogenic electron microscopy structures reveal a unique binding mode in which two AP-7-168 molecules pack within a pocket formed by transmembrane helices 3, 4 and 5 of two protomers, stabilizing a dimeric conformation that selectively prevents β-arrestin coupling. In cells, AP-7-168 robustly stabilizes β2AR dimerization and drives enlarged nanocluster formation. Combined with extensive functional studies, our findings identify an allosteric mechanism by which a small molecule biases β2AR signalling through dimerization, highlighting ligand-stabilized dimerization as a strategy for GPCR modulation.
(© 2026. The Author(s).)
Competing Interests: Competing interests: A patent on the reported compounds was submitted by J.L.B. and others in 2022. B.K.K. is a cofounder of and consultant for ConfometRx. The other authors declare no competing interests.
Σχόλια: Update of: bioRxiv. 2025 Oct 22:2025.10.21.683802. doi: 10.1101/2025.10.21.683802.. (PMID: 41279134)
Update of: Res Sq. 2025 Nov 26:rs.3.rs-8001844. doi: 10.21203/rs.3.rs-8001844/v1.. (PMID: 41356349)
References: Proc Natl Acad Sci U S A. 2018 Apr 10;115(15):3834-3839. (PMID: 29581292)
Nat Struct Mol Biol. 2022 Jul;29(7):688-697. (PMID: 35817871)
Science. 2020 Jul 31;369(6503):. (PMID: 32732395)
J Magn Reson. 2018 Nov;296:103-111. (PMID: 30241017)
Nat Chem Biol. 2020 Jul;16(7):749-755. (PMID: 32483378)
Bioconjug Chem. 2023 Apr 19;34(4):739-747. (PMID: 36919927)
J Am Chem Soc. 2021 Oct 27;143(42):17566-17576. (PMID: 34663067)
Magn Reson (Gott). 2020;1(2):209-224. (PMID: 34568875)
Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3684-9. (PMID: 10725388)
EMBO J. 2009 Nov 4;28(21):3315-28. (PMID: 19763081)
Drug Discov Today. 2021 Jan;26(1):189-199. (PMID: 33075471)
Nat Commun. 2026 Apr 03;17(1):. (PMID: 41932888)
Structure. 2016 Dec 6;24(12):2198-2206. (PMID: 27818102)
J Comput Chem. 2004 Oct;25(13):1605-12. (PMID: 15264254)
Nature. 2017 Jul 6;547(7661):68-73. (PMID: 28607487)
Proc Natl Acad Sci U S A. 2023 Aug;120(31):e2302668120. (PMID: 37490535)
Nat Methods. 2017 Mar;14(3):290-296. (PMID: 28165473)
Acta Crystallogr D Biol Crystallogr. 2010 Jan;66(Pt 1):12-21. (PMID: 20057044)
Nature. 2023 Aug;620(7974):676-681. (PMID: 37532940)
J Biol Chem. 2007 Apr 6;282(14):10576-84. (PMID: 17283075)
Cell. 2023 Mar 30;186(7):1465-1477.e18. (PMID: 37001505)
Cell Rep. 2025 Apr 22;44(4):115478. (PMID: 40158220)
Nat Methods. 2015 Oct;12(10):943-6. (PMID: 26280328)
Nature. 2011 Jul 19;477(7366):549-55. (PMID: 21772288)
IUCrJ. 2019 Jan 01;6(Pt 1):5-17. (PMID: 30713699)
Elife. 2021 Nov 03;10:. (PMID: 34730514)
Proc Natl Acad Sci U S A. 2011 Jul 12;108(28):11399-404. (PMID: 21697512)
Acta Crystallogr D Struct Biol. 2018 Jun 1;74(Pt 6):531-544. (PMID: 29872004)
Proc Natl Acad Sci U S A. 2025 Jan 7;122(1):e2421275121. (PMID: 39739811)
Nat Commun. 2019 May 20;10(1):2234. (PMID: 31110175)
ACS Chem Biol. 2021 Feb 19;16(2):371-379. (PMID: 33435665)
Sci Adv. 2018 Aug 24;4(8):eaat5218. (PMID: 30151430)
Nat Commun. 2025 Aug 11;16(1):7403. (PMID: 40790299)
Science. 2007 Nov 23;318(5854):1258-65. (PMID: 17962520)
Methods Enzymol. 2015;556:405-24. (PMID: 25857793)
Protein Sci. 2021 Jan;30(1):70-82. (PMID: 32881101)
Neuropsychopharmacology. 2000 Oct;23(4 Suppl):S19-31. (PMID: 11008064)
Nat Struct Mol Biol. 2013 Apr;20(4):419-25. (PMID: 23435379)
Nature. 2011 Jan 13;469(7329):175-80. (PMID: 21228869)
J Biol Chem. 2019 Sep 27;294(39):14215-14230. (PMID: 31399513)
Nat Commun. 2022 Oct 26;13(1):6365. (PMID: 36289206)
Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501. (PMID: 20383002)
Nature. 2020 Jul;583(7818):862-866. (PMID: 32555462)
J Med Chem. 2013 Sep 12;56(17):6542-59. (PMID: 23678887)
Nat Commun. 2025 Jan 2;16(1):310. (PMID: 39747115)
Nature. 2017 Oct 26;550(7677):543-547. (PMID: 29045395)
Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):213-21. (PMID: 20124702)
Cell. 2017 Apr 20;169(3):407-421.e16. (PMID: 28431242)
Thorax. 1995 May;50(5):497-504. (PMID: 7597661)
Nat Commun. 2025 Aug 27;16(1):7988. (PMID: 40866348)
Biochem J. 2021 Dec 22;478(24):4169-4185. (PMID: 34783343)
J Biol Chem. 1997 Oct 24;272(43):26959-64. (PMID: 9341132)
Magn Reson (Gott). 2020 Dec 09;1(2):285-299. (PMID: 37904822)
Br J Pharmacol. 2022 Oct;179(19):4692-4708. (PMID: 35732075)
Nat Commun. 2020 Apr 14;11(1):1772. (PMID: 32286308)
Trends Biochem Sci. 2020 Dec;45(12):1049-1064. (PMID: 32861513)
FEBS J. 2021 Apr;288(8):2461-2489. (PMID: 33871923)
Proc Natl Acad Sci U S A. 2025 Jan 7;122(1):e2421280121. (PMID: 39739805)
Mol Pharmacol. 2003 Jun;63(6):1256-72. (PMID: 12761335)
Cell. 2022 Nov 23;185(24):4560-4573.e19. (PMID: 36368322)
J Biol Chem. 1996 Jul 5;271(27):16384-92. (PMID: 8663163)
Nat Methods. 2020 Dec;17(12):1214-1221. (PMID: 33257830)
Sci Adv. 2025 Mar 21;11(12):eadq3971. (PMID: 40106559)
Nat Commun. 2022 Nov 11;13(1):6826. (PMID: 36369272)
Mol Cell Endocrinol. 2019 Mar 1;483:24-30. (PMID: 30610913)
Chest. 1995 Nov;108(5):1235-9. (PMID: 7587422)
Nat Rev Mol Cell Biol. 2018 Oct;19(10):638-653. (PMID: 30104700)
J Struct Biol. 2012 Dec;180(3):519-30. (PMID: 23000701)
Substance Nomenclature: 0 (Receptors, Adrenergic, beta-2)
0 (Ligands)
0 (beta-Arrestins)
Entry Date(s): Date Created: 20260820 Date Completed: 20261008 Latest Revision: 20261010
Update Code: 20261010
PubMed Central ID: PMC13645619
DOI: 10.1038/s41586-026-10892-y
PMID: 42618785
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:1476-4687
DOI:10.1038/s41586-026-10892-y