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TitleXanomeline displays concomitant orthosteric and allosteric binding modes at the M mAChR.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 5440, Year 2023
Publish dateSep 6, 2023
AuthorsWessel A C Burger / Vi Pham / Ziva Vuckovic / Alexander S Powers / Jesse I Mobbs / Yianni Laloudakis / Alisa Glukhova / Denise Wootten / Andrew B Tobin / Patrick M Sexton / Steven M Paul / Christian C Felder / Radostin Danev / Ron O Dror / Arthur Christopoulos / Celine Valant / David M Thal /
PubMed AbstractThe M muscarinic acetylcholine receptor (M mAChR) has emerged as a drug target of high therapeutic interest due to its expression in regions of the brain involved in the regulation of psychosis, ...The M muscarinic acetylcholine receptor (M mAChR) has emerged as a drug target of high therapeutic interest due to its expression in regions of the brain involved in the regulation of psychosis, cognition, and addiction. The mAChR agonist, xanomeline, has provided significant improvement in the Positive and Negative Symptom Scale (PANSS) scores in a Phase II clinical trial for the treatment of patients suffering from schizophrenia. Here we report the active state cryo-EM structure of xanomeline bound to the human M mAChR in complex with the heterotrimeric G transducer protein. Unexpectedly, two molecules of xanomeline were found to concomitantly bind to the monomeric M mAChR, with one molecule bound in the orthosteric (acetylcholine-binding) site and a second molecule in an extracellular vestibular allosteric site. Molecular dynamic simulations supports the structural findings, and pharmacological validation confirmed that xanomeline acts as a dual orthosteric and allosteric ligand at the human M mAChR. These findings provide a basis for further understanding xanomeline's complex pharmacology and highlight the myriad of ways through which clinically relevant ligands can bind to and regulate GPCRs.
External linksNat Commun / PubMed:37673901 / PubMed Central
MethodsEM (single particle)
Resolution2.45 Å
Structure data

29524

8fx5

EMDB-29524, PDB-8fx5:
Human M4 muscarinic acetylcholine receptor complex with Gi1 and xanomeline
Method: EM (single particle) / Resolution: 2.45 Å

Chemicals

ChemComp-XNO:
xanomeline

ChemComp-HOH:
WATER / Water

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN/SIGNALING PROTEIN / 7 transmembrane receptor / SIGNALING PROTEIN-IMMUNE SYSTEM complex / MEMBRANE PROTEIN / MEMBRANE PROTEIN-SIGNALING PROTEIN-IMMUNE SYSTEM complex / MEMBRANE PROTEIN-SIGNALING PROTEIN complex

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