Structural insights into the high basal activity and inverse agonism of the orphan receptor GPR6 implicated in Parkinson’s disease
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<sub>s</sub> 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.
Authors
- Carol V. Robinson (ORCID: https://orcid.org/0000-0001-7829-5505)
- Gye Won Han (ORCID: https://orcid.org/0000-0003-4107-835X)
- Hans H. Schiffer
- Hongyang Sun (ORCID: https://orcid.org/0009-0005-4424-4386)
- Anastasiia Sadybekov (ORCID: https://orcid.org/0000-0003-3925-983X)
- Tian Hua (ORCID: https://orcid.org/0000-0002-6132-2068)
- Joshua Bliesath
- Corinne A. Lutomski (ORCID: https://orcid.org/0000-0001-7509-103X)
- Nicola Brice (ORCID: https://orcid.org/0000-0003-4533-9369)
- Vsevolod Katritch (ORCID: https://orcid.org/0000-0003-3883-4505)
- Holger Monenschein
- Mahta Barekatain (ORCID: https://orcid.org/0000-0003-4178-684X)
- Jordy Homing Lam (ORCID: https://orcid.org/0000-0002-5496-6228)
- Linda C. Johansson (ORCID: https://orcid.org/0000-0003-4776-5142)
- Mark Carlton
- Vadim Cherezov (ORCID: https://orcid.org/0000-0002-5265-3914)
- Sean T. Murphy (ORCID: https://orcid.org/0009-0000-5404-6512)
- Hao Chang (ORCID: https://orcid.org/0000-0003-1684-8201)
- Petr Popov (ORCID: https://orcid.org/0000-0003-3745-7154)
- Kumar Singh Saikatendu (ORCID: https://orcid.org/0000-0001-6734-237X)
- Zhi‐Jie Liu (ORCID: https://orcid.org/0000-0001-7279-2893)
- Joseph Russo
Institutions
- University of Southern California (US)
- ShanghaiTech University (CN)
- CRUK/MRC Oxford Institute for Radiation Oncology (GB)
- Cambridge Environmental Research Consultants (United Kingdom) (GB)
- Convergent Science (United States) (US)
- Takeda (United States) (US)
Publication Details
- Journal
- Science Signaling
- Published
- 2024-12-03
- DOI
- https://doi.org/10.1126/scisignal.ado8741
- Citations
- 14
- Primary Topic
- Receptor Mechanisms and Signaling
- Type
- article
- Field-Weighted Citation Impact
- 3.27
Funders
- U.S. Department of Energy
- Stiftelsen för Strategisk Forskning
- Svenska Sällskapet för Medicinsk Forskning
- Vetenskapsrådet
- National Institutes of Health
- Office of Science
- Medical Research Council
- National Key Research and Development Program of China
- National Cancer Institute
- National Institute of General Medical Sciences
- Argonne National Laboratory