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8TYW

cryo-EM structure of GPR6-Gs-Nb35 complex

Summary for 8TYW
Entry DOI10.2210/pdb8tyw/pdb
EMDB information41729
DescriptorG-protein coupled receptor 6, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, ... (5 entities in total)
Functional Keywordsgpr6, gs, nb, cryo-em, membrane protein
Biological sourceHomo sapiens (human)
More
Total number of polymer chains5
Total formula weight146506.89
Authors
Primary citationBarekatain, M.,Johansson, L.C.,Lam, J.H.,Chang, H.,Sadybekov, A.V.,Han, G.W.,Russo, J.,Bliesath, J.,Brice, N.L.,Carlton, M.B.L.,Saikatendu, K.S.,Sun, H.,Murphy, S.T.,Monenschein, H.,Schiffer, H.H.,Popov, P.,Lutomski, C.A.,Robinson, C.V.,Liu, Z.J.,Hua, T.,Katritch, V.,Cherezov, V.
Structural insights into the high basal activity and inverse agonism of the orphan receptor GPR6 implicated in Parkinson's disease.
Sci.Signal., 17:-, 2024
Cited by
PubMed 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 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.
PubMed: 39626010
DOI: 10.1126/scisignal.ado8741
PDB entries with the same primary citation
Experimental method
ELECTRON MICROSCOPY (3.43 Å)
Structure validation

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