8fx5
Human M4 muscarinic acetylcholine receptor complex with Gi1 and xanomeline
Structural highlights
FunctionACM4_HUMAN The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is inhibition of adenylate cyclase. Publication Abstract from PubMedThe M(4) muscarinic acetylcholine receptor (M(4) 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(4) mAChR in complex with the heterotrimeric G(i1) transducer protein. Unexpectedly, two molecules of xanomeline were found to concomitantly bind to the monomeric M(4) 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(4) 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. Xanomeline displays concomitant orthosteric and allosteric binding modes at the M(4) mAChR.,Burger WAC, Pham V, Vuckovic Z, Powers AS, Mobbs JI, Laloudakis Y, Glukhova A, Wootten D, Tobin AB, Sexton PM, Paul SM, Felder CC, Danev R, Dror RO, Christopoulos A, Valant C, Thal DM Nat Commun. 2023 Sep 6;14(1):5440. doi: 10.1038/s41467-023-41199-5. PMID:37673901[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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