8SMV

GPR161 Gs heterotrimer

Summary for 8SMV

• Entry DOI: 10.2210/pdb8smv/pdb
• EMDB information: 40603
• Descriptor: G-protein coupled receptor 161, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, Nanobody 35, ... (6 entities in total)
• Functional Keywords: gpcr, orphan, active, hedgehog, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 154510.47

Authors

Hoppe, N.,Manglik, A.,Harrison, S. (deposition date: 2023-04-26, release date: 2024-02-21, Last modification date: 2024-10-16)

Primary citation

Hoppe, N.,Harrison, S.,Hwang, S.H.,Chen, Z.,Karelina, M.,Deshpande, I.,Suomivuori, C.M.,Palicharla, V.R.,Berry, S.P.,Tschaikner, P.,Regele, D.,Covey, D.F.,Stefan, E.,Marks, D.S.,Reiter, J.F.,Dror, R.O.,Evers, A.S.,Mukhopadhyay, S.,Manglik, A.
GPR161 structure uncovers the redundant role of sterol-regulated ciliary cAMP signaling in the Hedgehog pathway.
Nat.Struct.Mol.Biol., 31:667-677, 2024

PubMed Abstract: The orphan G protein-coupled receptor (GPCR) GPR161 plays a central role in development by suppressing Hedgehog signaling. The fundamental basis of how GPR161 is activated remains unclear. Here, we determined a cryogenic-electron microscopy structure of active human GPR161 bound to heterotrimeric G. This structure revealed an extracellular loop 2 that occupies the canonical GPCR orthosteric ligand pocket. Furthermore, a sterol that binds adjacent to transmembrane helices 6 and 7 stabilizes a GPR161 conformation required for G coupling. Mutations that prevent sterol binding to GPR161 suppress G-mediated signaling. These mutants retain the ability to suppress GLI2 transcription factor accumulation in primary cilia, a key function of ciliary GPR161. By contrast, a protein kinase A-binding site in the GPR161 C terminus is critical in suppressing GLI2 ciliary accumulation. Our work highlights how structural features of GPR161 interface with the Hedgehog pathway and sets a foundation to understand the role of GPR161 function in other signaling pathways.

PubMed: 38326651
DOI: 10.1038/s41594-024-01223-8

Experimental method

ELECTRON MICROSCOPY (2.74 Å)