7y26 | pdb_00007y26
Cryo-EM structure of the octreotide-bound SSTR2-miniGq-scFv16 complex
Structural highlights
FunctionGBB1_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction.[1] Publication Abstract from PubMedG 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(i/o) pathway, somatostatin receptor 2 and 5 (SSTR2 and SSTR5) couple to the G(q/11) pathway and show that smaller ligands preferentially activate the G(i/o) pathway. We further determined cryo-electron microscopy structures of the SSTR2âG(o) and SSTR2âG(q) 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(q/11) coupling but not G(i/o) coupling. Our studies facilitate the design of drugs with selective G protein signaling to improve therapeutic efficacy. Molecular basis for the selective G protein signaling of somatostatin receptors.,Chen S, Teng X, Zheng S Nat Chem Biol. 2023 Feb;19(2):133-140. doi: 10.1038/s41589-022-01130-3. Epub 2022 , Sep 22. PMID:36138141[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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