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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\u2019s disease in clinical trials. In addition, we obtained a cryo\u2013electron microscopy structure of the signaling complex between GPR6 and its cognate G\n                    <jats:sub>s<\/jats:sub>\n                    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.\n                  <\/jats:p>","DOI":"10.1126\/scisignal.ado8741","type":"journal-article","created":{"date-parts":[[2024,12,3]],"date-time":"2024-12-03T13:58:17Z","timestamp":1733234297000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":23,"title":["Structural insights into the high basal activity and inverse agonism of the orphan receptor GPR6 implicated in Parkinson\u2019s disease"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4178-684X","authenticated-orcid":true,"given":"Mahta","family":"Barekatain","sequence":"first","affiliation":[{"name":"Bridge Institute, USC Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA 90089, USA."},{"name":"Department of Chemistry, University of Southern California, Los Angeles, CA 90089, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda C.","family":"Johansson","sequence":"additional","affiliation":[{"name":"Bridge Institute, USC Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA 90089, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5496-6228","authenticated-orcid":true,"given":"Jordy H.","family":"Lam","sequence":"additional","affiliation":[{"name":"Bridge Institute, USC Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA 90089, USA."},{"name":"Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA 90089, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1684-8201","authenticated-orcid":true,"given":"Hao","family":"Chang","sequence":"additional","affiliation":[{"name":"iHuman Institute, ShanghaiTech University, Shanghai 201210, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3925-983X","authenticated-orcid":true,"given":"Anastasiia V.","family":"Sadybekov","sequence":"additional","affiliation":[{"name":"Bridge Institute, USC Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA 90089, USA."},{"name":"Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA 90089, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4107-835X","authenticated-orcid":true,"given":"Gye Won","family":"Han","sequence":"additional","affiliation":[{"name":"Bridge Institute, USC Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA 90089, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Russo","sequence":"additional","affiliation":[{"name":"Takeda Development Center Americas Inc., San Diego, CA 92121, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Bliesath","sequence":"additional","affiliation":[{"name":"Takeda Development Center Americas Inc., San Diego, CA 92121, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola L.","family":"Brice","sequence":"additional","affiliation":[{"name":"Cerevance, Cambridge CB4 0PZ, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark B. 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