8FX5

Human M4 muscarinic acetylcholine receptor complex with Gi1 and xanomeline

Summary for 8FX5

• Entry DOI: 10.2210/pdb8fx5/pdb
• EMDB information: 29524
• Descriptor: Muscarinic acetylcholine receptor M4, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (7 entities in total)
• Functional Keywords: 7 transmembrane receptor, signaling protein-immune system complex, membrane protein, membrane protein-signaling protein-immune system complex, membrane protein-signaling protein complex, membrane protein/signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 153174.46

Authors

Vuckovic, Z.,Mobbs, J.I.,Glukhova, A.,Sexton, P.M.,Danev, R.,Thal, D.M. (deposition date: 2023-01-23, release date: 2023-09-13)

Primary citation

Burger, W.A.C.,Pham, V.,Vuckovic, Z.,Powers, A.S.,Mobbs, J.I.,Laloudakis, Y.,Glukhova, A.,Wootten, D.,Tobin, A.B.,Sexton, P.M.,Paul, S.M.,Felder, C.C.,Danev, R.,Dror, R.O.,Christopoulos, A.,Valant, C.,Thal, D.M.
Xanomeline displays concomitant orthosteric and allosteric binding modes at the M 4 mAChR.
Nat Commun, 14:5440-5440, 2023

PubMed Abstract: 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.

PubMed: 37673901
DOI: 10.1038/s41467-023-41199-5

Experimental method

ELECTRON MICROSCOPY (2.45 Å)