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TitleCryo-EM reveals an extrahelical allosteric binding site at the M mAChR.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 7046, Year 2025
Publish dateJul 31, 2025
AuthorsWessel A C Burger / Jesse I Mobbs / Bhavika Rana / Jinan Wang / Keya Joshi / Patrick R Gentry / Mahmuda Yeasmin / Hariprasad Venugopal / Aaron M Bender / Craig W Lindsley / Yinglong Miao / Arthur Christopoulos / Celine Valant / David M Thal /
PubMed AbstractThe M muscarinic acetylcholine receptor (M mAChR) represents a promising therapeutic target for neurological disorders. However, the high conservation of its orthosteric binding site poses ...The M muscarinic acetylcholine receptor (M mAChR) represents a promising therapeutic target for neurological disorders. However, the high conservation of its orthosteric binding site poses significant challenges for drug development. While selective positive allosteric modulators (PAMs) offer a potential solution, a structural understanding of the M mAChR and its allosteric binding sites remains limited. Here, we present a 2.8 Å cryo-electron microscopy structure of the M mAChR complexed with heterotrimeric G protein and the agonist iperoxo, completing the active-state structural characterization of the mAChR family. To identify the binding site of M-selective PAMs, we implement an integrated approach combining mutagenesis, pharmacological assays, structural biology, and molecular dynamics simulations. Our mutagenesis studies reveal that selective M PAMs bind outside previously characterized M mAChR allosteric sites. Subsequently, we obtain a 2.1 Å structure of M mAChR co-bound with acetylcholine and the selective PAM VU6007678, revealing an allosteric pocket at the extrahelical interface between transmembrane domains 3 and 4 that is confirmed through mutagenesis and simulations. These findings demonstrate the diverse mechanisms of allosteric regulation in mAChRs and highlight the value of integrating pharmacological and structural approaches to identify allosteric binding sites.
External linksNat Commun / PubMed:40745154 / PubMed Central
MethodsEM (single particle)
Resolution2.06 - 2.79 Å
Structure data

48110

9ejz

EMDB-48110, PDB-9ejz:
Human M5 muscarinic acetylcholine receptor complex with mini-Gq, agonist acetylcholine and positive allosteric modulator VU6007678
Method: EM (single particle) / Resolution: 2.06 Å

48111

9ek0

EMDB-48111, PDB-9ek0:
Human M5 muscarinic acetylcholine receptor complex with mini-Gq and iperoxo
Method: EM (single particle) / Resolution: 2.79 Å

Chemicals

PDB-1bks:
TRYPTOPHAN SYNTHASE (E.C.4.2.1.20) FROM SALMONELLA TYPHIMURIUM

ChemComp-ACH:
ACETYLCHOLINE / neurotransmitter*YM

ChemComp-HOH:
WATER

ChemComp-IXO:
4-(4,5-dihydro-1,2-oxazol-3-yloxy)-N,N,N-trimethylbut-2-yn-1-aminium

Source
  • homo sapiens (human)
  • lama glama (llama)
  • rattus norvegicus (Norway rat)
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / G protein-coupled receptor / acetylcholine binding / seven transmembrane protein

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