Xanomeline displays concomitant orthosteric and allosteric binding modes at the M4 mAChR
Abstract The M4 muscarinic acetylcholine receptor (M4 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...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-09-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-41199-5 |
| _version_ | 1797558454929326080 |
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| author | Wessel 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 |
| author_facet | Wessel 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 |
| author_sort | Wessel A. C. Burger |
| collection | DOAJ |
| description | Abstract The M4 muscarinic acetylcholine receptor (M4 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 M4 mAChR in complex with the heterotrimeric Gi1 transducer protein. Unexpectedly, two molecules of xanomeline were found to concomitantly bind to the monomeric M4 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 M4 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. |
| first_indexed | 2024-03-10T17:31:39Z |
| format | Article |
| id | doaj.art-7484d1906038449ebf83ab0a1980953a |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:31:39Z |
| publishDate | 2023-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-7484d1906038449ebf83ab0a1980953a2023-11-20T10:00:04ZengNature PortfolioNature Communications2041-17232023-09-0114111110.1038/s41467-023-41199-5Xanomeline displays concomitant orthosteric and allosteric binding modes at the M4 mAChRWessel A. C. Burger0Vi Pham1Ziva Vuckovic2Alexander S. Powers3Jesse I. Mobbs4Yianni Laloudakis5Alisa Glukhova6Denise Wootten7Andrew B. Tobin8Patrick M. Sexton9Steven M. Paul10Christian C. Felder11Radostin Danev12Ron O. Dror13Arthur Christopoulos14Celine Valant15David M. Thal16Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash UniversityDrug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash UniversityDrug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash UniversityDepartment of Chemistry, Stanford UniversityDrug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash UniversityDepartment of Chemistry, Stanford UniversityDrug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash UniversityDrug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash UniversityThe Advanced Research Centre (ARC), Centre for Translational Science, School of Biomolecular Sciences, College of Medical, Veterinary and Life Sciences, University of GlasgowDrug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash UniversityKaruna TherapeuticsKaruna TherapeuticsGraduate School of Medicine, University of TokyoDepartments of Computer Science, Structural Biology, and Molecular and Cellular Physiology, Stanford UniversityDrug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash UniversityDrug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash UniversityDrug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash UniversityAbstract The M4 muscarinic acetylcholine receptor (M4 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 M4 mAChR in complex with the heterotrimeric Gi1 transducer protein. Unexpectedly, two molecules of xanomeline were found to concomitantly bind to the monomeric M4 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 M4 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.https://doi.org/10.1038/s41467-023-41199-5 |
| spellingShingle | Wessel 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 Xanomeline displays concomitant orthosteric and allosteric binding modes at the M4 mAChR Nature Communications |
| title | Xanomeline displays concomitant orthosteric and allosteric binding modes at the M4 mAChR |
| title_full | Xanomeline displays concomitant orthosteric and allosteric binding modes at the M4 mAChR |
| title_fullStr | Xanomeline displays concomitant orthosteric and allosteric binding modes at the M4 mAChR |
| title_full_unstemmed | Xanomeline displays concomitant orthosteric and allosteric binding modes at the M4 mAChR |
| title_short | Xanomeline displays concomitant orthosteric and allosteric binding modes at the M4 mAChR |
| title_sort | xanomeline displays concomitant orthosteric and allosteric binding modes at the m4 machr |
| url | https://doi.org/10.1038/s41467-023-41199-5 |
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