+Search query
-Structure paper
Title | Molecular basis for the selective G protein signaling of somatostatin receptors. |
---|---|
Journal, issue, pages | Nat Chem Biol, Vol. 19, Issue 2, Page 133-140, Year 2023 |
Publish date | Sep 22, 2022 |
Authors | Sijia Chen / Xiao Teng / Sanduo Zheng / |
PubMed Abstract | G protein-coupled receptors (GPCRs) modulate every aspect of physiological functions mainly through activating heterotrimeric G proteins. A majority of GPCRs promiscuously couple to multiple G ...G protein-coupled receptors (GPCRs) modulate every aspect of physiological functions mainly through activating heterotrimeric G proteins. A majority of GPCRs promiscuously couple to multiple G protein subtypes. Here we validate that in addition to the well-known G pathway, somatostatin receptor 2 and 5 (SSTR2 and SSTR5) couple to the G pathway and show that smaller ligands preferentially activate the G pathway. We further determined cryo-electron microscopy structures of the SSTR2‒G and SSTR2‒G complexes bound to octreotide and SST-14. Structural and functional analysis revealed that G protein selectivity of SSTRs is not only determined by structural elements in the receptor-G protein interface, but also by the conformation of the agonist-binding pocket. Accordingly, smaller ligands fail to stabilize a broader agonist-binding pocket of SSTRs that is required for efficient G coupling but not G coupling. Our studies facilitate the design of drugs with selective G protein signaling to improve therapeutic efficacy. |
External links | Nat Chem Biol / PubMed:36138141 |
Methods | EM (single particle) |
Resolution | 3.25 - 3.48 Å |
Structure data | EMDB-33585, PDB-7y24: EMDB-33586, PDB-7y26: EMDB-33587, PDB-7y27: |
Chemicals | ChemComp-CLR: |
Source |
|
Keywords | STRUCTURAL PROTEIN / GPCR / somatostatin receptor / G protein / biased ligand |