{"doi":"10.1126/scisignal.ado8741","title":"Structural insights into the high basal activity and inverse agonism of the orphan receptor GPR6 implicated in Parkinson’s disease","abstract":"GPR6 is an orphan G protein–coupled receptor with high constitutive activity found in D2-type dopamine receptor–expressing medium spiny neurons of the striatopallidal pathway, which is aberrantly hyperactivated in Parkinson’s disease. Here, we solved crystal structures of GPR6 without the addition of a ligand (a pseudo-apo state) and in complex with two inverse agonists, including CVN424, which improved motor symptoms in patients with Parkinson’s disease in clinical trials. In addition, we obtained a cryo–electron microscopy structure of the signaling complex between GPR6 and its cognate G s heterotrimer. The pseudo-apo structure revealed a strong density in the orthosteric pocket of GPR6 corresponding to a lipid-like endogenous ligand. A combination of site-directed mutagenesis, native mass spectrometry, and computer modeling suggested potential mechanisms for high constitutive activity and inverse agonism in GPR6 and identified a series of lipids and ions bound to the receptor. The structures and results obtained in this study could guide the rational design of drugs that modulate GPR6 signaling.","journal":"Science Signaling","year":2024,"id":430830,"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":18,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9445,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1234203,"name":"Linda C. Johansson","orcid":"0000-0003-4776-5142","position":1,"is_corresponding":false},{"id":1022743,"name":"Jordy Homing Lam","orcid":"0000-0002-5496-6228","position":2,"is_corresponding":false},{"id":382068,"name":"Hao Chang","orcid":null,"position":3,"is_corresponding":false},{"id":713859,"name":"Anastasiia Sadybekov","orcid":"0000-0003-3925-983X","position":4,"is_corresponding":false},{"id":266169,"name":"Gye Won Han","orcid":"0000-0003-4107-835X","position":5,"is_corresponding":false},{"id":349503,"name":"Joseph Russo","orcid":null,"position":6,"is_corresponding":false},{"id":1234660,"name":"Joshua Bliesath","orcid":null,"position":7,"is_corresponding":false},{"id":1234204,"name":"Nicola Brice","orcid":"0000-0003-4533-9369","position":8,"is_corresponding":false},{"id":1234661,"name":"Mark Carlton","orcid":null,"position":9,"is_corresponding":false},{"id":634698,"name":"Kumar Singh Saikatendu","orcid":"0000-0001-6734-237X","position":10,"is_corresponding":false},{"id":1234662,"name":"Hukai Sun","orcid":null,"position":11,"is_corresponding":false},{"id":1234205,"name":"Sean T. Murphy","orcid":"0009-0000-5404-6512","position":12,"is_corresponding":false},{"id":1234663,"name":"Holger Monenschein","orcid":null,"position":13,"is_corresponding":false},{"id":1234664,"name":"Hans H. Schiffer","orcid":null,"position":14,"is_corresponding":false},{"id":713865,"name":"Petr Popov","orcid":"0000-0003-3745-7154","position":15,"is_corresponding":false},{"id":409216,"name":"Corinne A. Lutomski","orcid":"0000-0001-7509-103X","position":16,"is_corresponding":false},{"id":250509,"name":"Carol V. Robinson","orcid":"0000-0001-7829-5505","position":17,"is_corresponding":false},{"id":1023747,"name":"Zhi‐Jie Liu","orcid":"0000-0001-7279-2893","position":18,"is_corresponding":false},{"id":1016523,"name":"Tian Hua","orcid":"0000-0002-6132-2068","position":19,"is_corresponding":false},{"id":40489,"name":"Vsevolod Katritch","orcid":"0000-0003-3883-4505","position":20,"is_corresponding":false},{"id":198890,"name":"Vadim Cherezov","orcid":"0000-0002-5265-3914","position":21,"is_corresponding":false},{"id":832072,"name":"Mahta Barekatain","orcid":"0000-0003-4178-684X","position":0,"is_corresponding":true}],"reference_count":84,"raw_metadata":null,"created_at":"2026-07-19T01:59:20.861374Z","pmid":"39626010","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":[]}