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Structure paper

TitleStructural and dynamic insights into supra-physiological activation and allosteric modulation of a muscarinic acetylcholine receptor.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 376, Year 2023
Publish dateJan 23, 2023
AuthorsJun Xu / Qinggong Wang / Harald Hübner / Yunfei Hu / Xiaogang Niu / Haoqing Wang / Shoji Maeda / Asuka Inoue / Yuyong Tao / Peter Gmeiner / Yang Du / Changwen Jin / Brian K Kobilka /
PubMed AbstractThe 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, ...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.
External linksNat Commun / PubMed:36690613 / PubMed Central
MethodsEM (single particle)
Resolution3.16 - 3.32 Å
Structure data

25748

7t8x

EMDB-25748, PDB-7t8x:
Cryo-EM structure of ACh-bound M2R-Go signaling complex in S1 state
Method: EM (single particle) / Resolution: 3.21 Å

25749

7t90

EMDB-25749, PDB-7t90:
Cryo-EM structure of ACh-bound M2R-Go signaling complex in S2 state
Method: EM (single particle) / Resolution: 3.32 Å

25751

7t94

EMDB-25751, PDB-7t94:
Cryo-EM structure of S1 state ACh-bound M2R-Go signaling complex with a PAM
Method: EM (single particle) / Resolution: 3.16 Å

25752

7t96

EMDB-25752, PDB-7t96:
Cryo-EM structure of S2 state ACh-bound M2R-Go signaling complex with a PAM
Method: EM (single particle) / Resolution: 3.22 Å

Chemicals

ChemComp-ACH:
ACETYLCHOLINE / neurotransmitter*YM / Acetylcholine

ChemComp-HOH:
WATER / Water

ChemComp-2CU:
3-amino-5-chloro-N-cyclopropyl-4-methyl-6-[2-(4-methylpiperazin-1-yl)-2-oxoethoxy]thieno[2,3-b]pyridine-2-carboxamide

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / GPCR / signaling complex / muscarinic receptor / acetylcholine

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