7y24
From Proteopedia
Cryo-EM structure of the octreotide-bound SSTR2-miniGo-scFv16 complex
Structural highlights
DiseaseGNAO_HUMAN Early infantile epileptic encephalopathy. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. FunctionGNAO_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. The G(o) protein function is not clear. Stimulated by RGS14. 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 Gi/o pathway, somatostatin receptor 2 and 5 (SSTR2 and SSTR5) couple to the Gq/11 pathway and show that smaller ligands preferentially activate the Gi/o pathway. We further determined cryo-electron microscopy structures of the SSTR2Go and SSTR2Gq 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 Gq/11 coupling but not Gi/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. 2022 Sep 22. pii: 10.1038/s41589-022-01130-3. doi:, 10.1038/s41589-022-01130-3. PMID:36138141[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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