7XJL

Cryo-EM structure of the spexin-bound GALR2-miniGq complex

Summary for 7XJL

• Entry DOI: 10.2210/pdb7xjl/pdb
• EMDB information: 33231
• Descriptor: spexin, Guanine nucleotide-binding protein G(q) subunit alpha, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ... (6 entities in total)
• Functional Keywords: gpcr, galanin receptor 2, minigq, spexin, signaling protein
• Biological source: Homo sapiens; More
• Total number of polymer chains: 6
• Total formula weight: 144511.33

Authors

Jiang, W.,Zheng, S. (deposition date: 2022-04-18, release date: 2022-06-29, Last modification date: 2024-11-06)

Primary citation

Jiang, W.,Zheng, S.
Structural insights into galanin receptor signaling.
Proc.Natl.Acad.Sci.USA, 119:e2121465119-e2121465119, 2022

PubMed Abstract: Galanin is a biologically active neuropeptide, and functions through three distinct G protein–coupled receptors (GPCRs), namely GALR1, GALR2, and GALR3. GALR signaling plays important roles in regulating various physiological processes such as energy metabolism, neuropathic pain, epileptic activity, and sleep homeostasis. GALR1 and GALR3 signal through the Gi/o pathway, whereas GALR2 signals mainly through the Gq/11 pathway. However, the molecular basis for galanin recognition and G protein selectivity of GALRs remains poorly understood. Here, we report the cryoelectron microscopy structures of the GALR1-Go and the GALR2-Gq complexes bound to the endogenous ligand galanin or spexin. The galanin peptide mainly adopts an alpha helical structure, which binds at the extracellular vestibule of the receptors, nearly parallel to the membrane plane without penetrating deeply into the receptor core. Structural analysis combined with functional studies reveals important structural determinants for the G protein selectivity of GALRs as well as other class A GPCRs. In addition, we show that the zinc ion is a negative allosteric regulator of GALR1 but not GALR2. Our studies provide insight into the mechanisms of G protein selectivity of GPCRs and highlight a potential function of the neuromodulator zinc ion as a modulator of GPCR signaling in the central nervous system.

PubMed: 35594396
DOI: 10.1073/pnas.2121465119

Experimental method

ELECTRON MICROSCOPY (3.5 Å)