7Y26

Cryo-EM structure of the octreotide-bound SSTR2-miniGq-scFv16 complex

Summary for 7Y26

• Entry DOI: 10.2210/pdb7y26/pdb
• Related: 7Y24
• EMDB information: 33586
• Descriptor: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Engineered Guanine nucleotide-binding protein G(q) subunit alpha, Octreotide, ... (6 entities in total)
• Functional Keywords: gpcr, g protein, biased ligand, structural protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 139363.11

Authors

Chen, S.,Zheng, S. (deposition date: 2022-06-09, release date: 2022-10-19, Last modification date: 2024-11-13)

Primary citation

Chen, S.,Teng, X.,Zheng, S.
Molecular basis for the selective G protein signaling of somatostatin receptors.
Nat.Chem.Biol., 19:133-140, 2023

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 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.

PubMed: 36138141
DOI: 10.1038/s41589-022-01130-3

Experimental method

ELECTRON MICROSCOPY (3.3 Å)