Structural and dynamic insights into supra-physiological activation and allosteric modulation of a muscarinic acetylcholine receptor.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
23 01 2023
23 01 2023
Historique:
received:
02
07
2022
accepted:
21
12
2022
entrez:
23
1
2023
pubmed:
24
1
2023
medline:
26
1
2023
Statut:
epublish
Résumé
The M2 muscarinic receptor (M2R) is a prototypical G-protein-coupled receptor (GPCR) that serves as a model system for understanding GPCR regulation by both orthosteric and allosteric ligands. Here, we investigate the mechanisms governing M2R signaling versatility using cryo-electron microscopy (cryo-EM) and NMR spectroscopy, focusing on the physiological agonist acetylcholine and a supra-physiological agonist iperoxo, as well as a positive allosteric modulator LY2119620. These studies reveal that acetylcholine stabilizes a more heterogeneous M2R-G-protein complex than iperoxo, where two conformers with distinctive G-protein orientations were determined. We find that LY2119620 increases the affinity for both agonists, but differentially modulates agonists efficacy in G-protein and β-arrestin pathways. Structural and spectroscopic analysis suggest that LY211620 stabilizes distinct intracellular conformational ensembles from agonist-bound M2R, which may enhance β-arrestin recruitment while impairing G-protein activation. These results highlight the role of conformational dynamics in the complex signaling behavior of GPCRs, and could facilitate design of better drugs.
Identifiants
pubmed: 36690613
doi: 10.1038/s41467-022-35726-z
pii: 10.1038/s41467-022-35726-z
pmc: PMC9870890
doi:
Substances chimiques
iperoxo
0
Acetylcholine
N9YNS0M02X
Receptors, Muscarinic
0
Receptor, Muscarinic M2
0
Receptors, G-Protein-Coupled
0
GTP-Binding Proteins
EC 3.6.1.-
Ligands
0
beta-Arrestins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
376Informations de copyright
© 2023. The Author(s).
Références
J Mol Cell Cardiol. 1990 Mar;22(3):343-51
pubmed: 2113101
J Struct Biol. 2021 Jun;213(2):107702
pubmed: 33582281
Cell Res. 2019 Dec;29(12):971-983
pubmed: 31776446
Nat Methods. 2017 Apr;14(4):331-332
pubmed: 28250466
Nature. 2021 Jan;589(7843):620-626
pubmed: 33408414
Cell Res. 2021 Aug;31(8):932-934
pubmed: 33664408
Mol Pharmacol. 2014 Jul;86(1):106-15
pubmed: 24807965
Nature. 2013 Nov 14;503(7475):295-9
pubmed: 24121438
Mol Cell. 2019 Jul 11;75(1):53-65.e7
pubmed: 31103421
Cell. 2021 Apr 1;184(7):1884-1894.e14
pubmed: 33743210
Trends Cell Biol. 2020 Sep;30(9):736-747
pubmed: 32622699
Cell. 2021 Feb 18;184(4):931-942.e18
pubmed: 33571431
Nature. 2019 Aug;572(7767):80-85
pubmed: 31243364
Science. 2019 May 10;364(6440):552-557
pubmed: 31073061
Cell. 2013 Jan 31;152(3):532-42
pubmed: 23374348
Nat Commun. 2021 Nov 4;12(1):6410
pubmed: 34737341
J Biol Chem. 2006 Jan 13;281(2):1261-73
pubmed: 16280323
Nature. 2016 Jul 7;535(7610):182-6
pubmed: 27362234
J Biol Chem. 2015 Aug 7;290(32):19478-88
pubmed: 26100627
J Comput Chem. 2004 Oct;25(13):1605-12
pubmed: 15264254
Nat Commun. 2020 Feb 3;11(1):669
pubmed: 32015348
Nat Commun. 2016 Jul 26;7:12298
pubmed: 27457610
Bio Protoc. 2017 Apr 20;7(8):
pubmed: 28480316
Nature. 2017 Jul 6;547(7661):68-73
pubmed: 28607487
J Struct Biol. 2015 Nov;192(2):216-21
pubmed: 26278980
Nat Methods. 2017 Mar;14(3):290-296
pubmed: 28165473
Nat Chem Biol. 2020 May;16(5):507-512
pubmed: 32152538
Acta Crystallogr D Biol Crystallogr. 2010 Jan;66(Pt 1):12-21
pubmed: 20057044
J Biol Chem. 1998 Feb 27;273(9):5323-30
pubmed: 9478991
Cell. 2019 Jan 24;176(3):448-458.e12
pubmed: 30639101
Cell. 2019 Jan 24;176(3):468-478.e11
pubmed: 30639099
RSC Adv. 2021 Apr 7;11(21):12559-12567
pubmed: 35423811
Nat Commun. 2018 Jan 15;9(1):194
pubmed: 29335412
J Biol Chem. 2007 Nov 30;282(48):34968-76
pubmed: 17890226
Sci Adv. 2021 May 21;7(21):
pubmed: 34020960
Nature. 2013 Dec 5;504(7478):101-6
pubmed: 24256733
Nat Commun. 2020 Feb 14;11(1):885
pubmed: 32060286
Nat Methods. 2012 Jun 28;9(7):676-82
pubmed: 22743772
Nat Commun. 2021 Feb 5;12(1):815
pubmed: 33547286
Nat Commun. 2018 Sep 13;9(1):3712
pubmed: 30213947
Mol Pharmacol. 2012 Jan;81(1):41-52
pubmed: 21989256
Nature. 2016 Feb 11;530(7589):237-41
pubmed: 26840483
IUCrJ. 2020 Feb 22;7(Pt 2):294-305
pubmed: 32148857
Proc Natl Acad Sci U S A. 2018 Mar 6;115(10):E2419-E2428
pubmed: 29453275
Commun Biol. 2021 Jul 15;4(1):874
pubmed: 34267316
J Biol Chem. 1997 May 30;272(22):14152-8
pubmed: 9162044
Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501
pubmed: 20383002
Mol Cell. 2020 Nov 5;80(3):485-500.e7
pubmed: 33027691
Front Endocrinol (Lausanne). 2014 May 08;5:68
pubmed: 24847311
J Med Chem. 2017 Nov 22;60(22):9239-9250
pubmed: 29094937
J Biol Chem. 2006 Apr 21;281(16):10856-64
pubmed: 16492667
Nat Rev Drug Discov. 2014 Jul;13(7):549-60
pubmed: 24903776
Br J Pharmacol. 2013 May;169(2):357-70
pubmed: 23062057
J Biol Chem. 2010 Aug 13;285(33):25624-36
pubmed: 20551320
Nature. 2016 Mar 17;531(7594):335-40
pubmed: 26958838
Angew Chem Int Ed Engl. 2015 Dec 21;54(52):15771-6
pubmed: 26568421
Nat Struct Mol Biol. 2021 Mar;28(3):258-267
pubmed: 33633398
Bioorg Med Chem. 1999 Aug;7(8):1539-47
pubmed: 10482446
Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):213-21
pubmed: 20124702
Nat Rev Drug Discov. 2007 Sep;6(9):721-33
pubmed: 17762886
Science. 2020 Feb 21;367(6480):881-887
pubmed: 32079767
Curr Opin Struct Biol. 2016 Dec;41:83-89
pubmed: 27344006
Nat Struct Mol Biol. 2021 Aug;28(8):694-701
pubmed: 34354246
Mol Pharmacol. 2014 Nov;86(5):463-78
pubmed: 25061106
Nature. 2020 Mar;579(7798):297-302
pubmed: 31945772
Cell. 2016 Oct 20;167(3):739-749.e11
pubmed: 27720449
Nature. 2012 Jan 25;482(7386):547-51
pubmed: 22278061
Trends Pharmacol Sci. 2007 Aug;28(8):397-406
pubmed: 17629961
J Biol Chem. 2006 Aug 25;281(34):24506-11
pubmed: 16787921
Proc Jpn Acad Ser B Phys Biol Sci. 2013;89(6):226-56
pubmed: 23759942
Proc Natl Acad Sci U S A. 2007 May 1;104(18):7682-7
pubmed: 17452637
Nat Rev Drug Discov. 2013 Aug;12(8):630-44
pubmed: 23903222
Nat Rev Mol Cell Biol. 2018 Oct;19(10):638-653
pubmed: 30104700
Mol Pharmacol. 2013 Oct;84(4):528-40
pubmed: 23887926
J Struct Biol. 2012 Dec;180(3):519-30
pubmed: 23000701