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TitleStructural insights into the high basal activity and inverse agonism of the orphan receptor GPR6 implicated in Parkinson's disease.
Journal, issue, pagesSci Signal, Vol. 17, Issue 865, Page eado8741, Year 2024
Publish dateDec 3, 2024
AuthorsMahta Barekatain / Linda C Johansson / Jordy H Lam / Hao Chang / Anastasiia V Sadybekov / Gye Won Han / Joseph Russo / Joshua Bliesath / Nicola L Brice / Mark B L Carlton / Kumar S Saikatendu / Hukai Sun / Sean T Murphy / Holger Monenschein / Hans H Schiffer / Petr Popov / Corinne A Lutomski / Carol V Robinson / Zhi-Jie Liu / Tian Hua / Vsevolod Katritch / Vadim Cherezov /
PubMed AbstractGPR6 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 ...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 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.
External linksSci Signal / PubMed:39626010
MethodsEM (single particle) / X-ray diffraction
Resolution2.1 - 3.49 Å
Structure data

41729

8tyw

EMDB-41729, PDB-8tyw:
cryo-EM structure of GPR6-Gs-Nb35 complex
Method: EM (single particle) / Resolution: 3.43 Å

PDB-8t1v:
Crystal structure of orphan G protein-coupled receptor 6 with bound inverse agonist 3h
Method: X-RAY DIFFRACTION / Resolution: 2.6 Å

PDB-8t1w:
Crystal structure of orphan G protein-coupled receptor 6 with bound CVN424
Method: X-RAY DIFFRACTION / Resolution: 3.49 Å

PDB-8tf5:
Crystal structure of orphan G protein-coupled receptor 6, pseudoapo form
Method: X-RAY DIFFRACTION / Resolution: 2.1 Å

Chemicals


ChemComp, No image

ChemComp-XY8:
Unknown entry

ChemComp-NA:
Unknown entry

ChemComp-HOH:
WATER


ChemComp, No image

ChemComp-X7T:
Unknown entry

ChemComp-OLC:
(2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate

ChemComp-P15:
2,5,8,11,14,17-HEXAOXANONADECAN-19-OL

ChemComp-OLA:
OLEIC ACID

ChemComp-CLR:
CHOLESTEROL

Source
  • homo sapiens (human)
  • lama glama (llama)
  • escherichia coli (E. coli)
KeywordsMEMBRANE PROTEIN / Orphan GPCR / GPR6 / BRIL / inverse agonist / IAG3h / LCP / APS / Parkinson's Disease / CVN424 / synchrotron / pseudoapo form / active-like conformation / Gs / Nb / cryo-EM

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