{"doi":"10.1371/journal.pbio.3001295","title":"Structures of the human cholecystokinin 1 (CCK1) receptor bound to Gs and Gq mimetic proteins provide insight into mechanisms of G protein selectivity","abstract":"G protein-coupled receptors (GPCRs) are critical regulators of cellular function acting via heterotrimeric G proteins as their primary transducers with individual GPCRs capable of pleiotropic coupling to multiple G proteins. Structural features governing G protein selectivity and promiscuity are currently unclear. Here, we used cryo-electron microscopy (cryo-EM) to determine structures of the cholecystokinin (CCK) type 1 receptor (CCK1R) bound to the CCK peptide agonist, CCK-8 and 2 distinct transducer proteins, its primary transducer Gq, and the more weakly coupled Gs. As seen with other Gq/11-GPCR complexes, the Gq-α5 helix (αH5) bound to a relatively narrow pocket in the CCK1R core. Surprisingly, the backbone of the CCK1R and volume of the G protein binding pocket were essentially equivalent when Gs was bound, with the Gs αH5 displaying a conformation that arises from \"unwinding\" of the far carboxyl-terminal residues, compared to canonically Gs coupled receptors. Thus, integrated changes in the conformations of both the receptor and G protein are likely to play critical roles in the promiscuous coupling of individual GPCRs.","journal":"PLoS Biology","year":2021,"id":150880,"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":88,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9499,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":307914,"name":"Matthew J. Belousoff","orcid":"0000-0002-3229-474X","position":1,"is_corresponding":false},{"id":307915,"name":"Kaleeckal G. Harikumar","orcid":"0000-0003-0411-5334","position":2,"is_corresponding":false},{"id":307912,"name":"Sarah Piper","orcid":"0000-0001-5337-5197","position":3,"is_corresponding":false},{"id":641076,"name":"Xiaomeng Xu","orcid":"0000-0002-4896-5915","position":4,"is_corresponding":false},{"id":307918,"name":"Sebastian G. B. Furness","orcid":"0000-0001-8655-8221","position":5,"is_corresponding":false},{"id":347611,"name":"Hariprasad Venugopal","orcid":"0000-0001-5230-2973","position":6,"is_corresponding":false},{"id":307919,"name":"Arthur Christopoulos","orcid":"0000-0003-4442-3294","position":7,"is_corresponding":false},{"id":307920,"name":"Radostin Danev","orcid":"0000-0001-6406-8993","position":8,"is_corresponding":false},{"id":307921,"name":"Denise Wootten","orcid":"0000-0003-4563-1642","position":9,"is_corresponding":false},{"id":638378,"name":"David M. Thal","orcid":"0000-0002-0325-2524","position":10,"is_corresponding":false},{"id":307923,"name":"Laurence J. Miller","orcid":"0000-0002-4554-3872","position":11,"is_corresponding":false},{"id":307922,"name":"Patrick M. Sexton","orcid":"0000-0001-8902-2473","position":12,"is_corresponding":false},{"id":641075,"name":"Jesse I. Mobbs","orcid":"0000-0001-6979-1427","position":0,"is_corresponding":true}],"reference_count":76,"raw_metadata":null,"created_at":"2026-07-18T23:43:06.501849Z","pmid":"34086670","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":[]}