{"doi":"10.1101/2022.09.27.509640","title":"Pharmacological hallmarks of allostery at the M4 muscarinic receptor elucidated through structure and dynamics","abstract":"Abstract Allosteric modulation of G protein-coupled receptors (GPCRs) is a major paradigm in drug discovery. Despite decades of research, a molecular level understanding of the general principals that govern the myriad pharmacological effects exerted by GPCR allosteric modulators remains limited. The M 4 muscarinic acetylcholine receptor (M 4 mAChR) is a well-validated and clinically relevant allosteric drug target for several major psychiatric and cognitive disorders. Here, we present high-resolution cryo-electron microscopy structures of the M 4 mAChR bound to a cognate G i1 protein and the high affinity agonist, iperoxo, in the absence and presence of two different positive allosteric modulators, LY2033298 or VU0467154. We have also determined the structure of the M 4 mAChR-G i1 complex bound to its endogenous agonist, acetylcholine (ACh). Structural comparisons, together with molecular dynamics, mutagenesis, and pharmacological validations, have provided in-depth insights into the role of structure and dynamics in orthosteric and allosteric ligand binding, global mechanisms of receptor activation, cooperativity, probe-dependence, and species variability; all key hallmarks underpinning contemporary GPCR drug discovery.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":304406,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9592,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":267669,"name":"Jinan Wang","orcid":"0000-0003-0162-212X","position":1,"is_corresponding":false},{"id":924779,"name":"Vi Pham","orcid":"0000-0002-4647-2885","position":2,"is_corresponding":false},{"id":641075,"name":"Jesse I. Mobbs","orcid":"0000-0001-6979-1427","position":3,"is_corresponding":false},{"id":307914,"name":"Matthew J. Belousoff","orcid":"0000-0002-3229-474X","position":4,"is_corresponding":false},{"id":409068,"name":"Apurba Bhattarai","orcid":"0000-0002-9904-8906","position":5,"is_corresponding":false},{"id":997263,"name":"Wessel A. C. Burger","orcid":"0000-0003-2047-2593","position":6,"is_corresponding":false},{"id":997805,"name":"Geoff Thompson","orcid":null,"position":7,"is_corresponding":false},{"id":997806,"name":"Mahmuda Yeasmin","orcid":null,"position":8,"is_corresponding":false},{"id":997264,"name":"Katie Leach","orcid":"0000-0002-9280-1803","position":9,"is_corresponding":false},{"id":997265,"name":"Emma T. van der Westhuizen","orcid":"0000-0001-9165-8526","position":10,"is_corresponding":false},{"id":997266,"name":"Elham Khajehali","orcid":"0000-0002-3125-3831","position":11,"is_corresponding":false},{"id":997267,"name":"Yi-Lynn Liang","orcid":"0000-0001-6948-5550","position":12,"is_corresponding":false},{"id":307917,"name":"Alisa Glukhova","orcid":"0000-0003-4146-965X","position":13,"is_corresponding":false},{"id":307921,"name":"Denise Wootten","orcid":"0000-0003-4563-1642","position":14,"is_corresponding":false},{"id":352918,"name":"Craig W. Lindsley","orcid":"0000-0003-0168-1445","position":15,"is_corresponding":false},{"id":262333,"name":"Andrew B. Tobin","orcid":"0000-0002-1807-3123","position":16,"is_corresponding":false},{"id":307922,"name":"Patrick M. Sexton","orcid":"0000-0001-8902-2473","position":17,"is_corresponding":false},{"id":307920,"name":"Radostin Danev","orcid":"0000-0001-6406-8993","position":18,"is_corresponding":false},{"id":997268,"name":"Céline Valant","orcid":"0000-0002-2509-7465","position":19,"is_corresponding":false},{"id":267670,"name":"Yinglong Miao","orcid":"0000-0003-3714-1395","position":20,"is_corresponding":false},{"id":307919,"name":"Arthur Christopoulos","orcid":"0000-0003-4442-3294","position":21,"is_corresponding":false},{"id":638378,"name":"David M. Thal","orcid":"0000-0002-0325-2524","position":22,"is_corresponding":false},{"id":997804,"name":"Ziva Vuckovic","orcid":null,"position":0,"is_corresponding":true}],"reference_count":126,"raw_metadata":null,"created_at":"2026-07-19T00:32:32.651796Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}