PDBsum entry 7d76

Membrane protein

PDB id: 7d76

Contents

Protein chains

215 a.a.

338 a.a.

56 a.a.

265 a.a.

Ligands

PLM ×3

Y01

GXR

CLR ×2

References listed in PDB file

Key reference

• Title: Structures of the glucocorticoid-Bound adhesion receptor gpr97-G_o complex.
• Authors: Y.Q.Ping, C.Mao, P.Xiao, R.J.Zhao, Y.Jiang, Z.Yang, W.T.An, D.D.Shen, F.Yang, H.Zhang, C.Qu, Q.Shen, C.Tian, Z.J.Li, S.Li, G.Y.Wang, X.Tao, X.Wen, Y.N.Zhong, J.Yang, F.Yi, X.Yu, H.E.Xu, Y.Zhang, J.P.Sun.
• Ref.: Nature, 2021, 589, 620-626. [DOI no: 10.1038/s41586-020-03083-w]
• PubMed id: 33408414

Abstract

Adhesion G-protein-coupled receptors (GPCRs) are a major family of GPCRs, but limited knowledge of their ligand regulation or structure is available^1-3. Here we report that glucocorticoid stress hormones activate adhesion G-protein-coupled receptor G3 (ADGRG3; also known as GPR97)^4-6, a prototypical adhesion GPCR. The cryo-electron microscopy structures of GPR97-G_o complexes bound to the anti-inflammatory drug beclomethasone or the steroid hormone cortisol revealed that glucocorticoids bind to a pocket within the transmembrane domain. The steroidal core of glucocorticoids is packed against the 'toggle switch' residue W^6.53, which senses the binding of a ligand and induces activation of the receptor. Active GPR97 uses a quaternary core and HLY motif to fasten the seven-transmembrane bundle and to mediate G protein coupling. The cytoplasmic side of GPR97 has an open cavity, where all three intracellular loops interact with the G_o protein, contributing to the high basal activity of GRP97. Palmitoylation at the cytosolic tail of the G_o protein was found to be essential for efficient engagement with GPR97 but is not observed in other solved GPCR complex structures. Our work provides a structural basis for ligand binding to the seven-transmembrane domain of an adhesion GPCR and subsequent G protein coupling.