8fx5

Human M4 muscarinic acetylcholine receptor complex with Gi1 and xanomeline

spinqualitylabelsall models 8fx5, resolution 2.45Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8fx5 is a 5 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 2.45Å Ligands: XNO Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function ACM4_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 PubMed The 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Transducin 3D structures

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