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Molecular basis for the selective G protein signaling of somatostatin receptors.

Chen S, Teng X, Zheng S
Nat Chem Biol (2022)
Related entries: 7y24, 7y26

Cited: 5 times
EuropePMC logo PMID: 36138141

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 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 SSTR2‒Go and SSTR2‒Gq 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.

Articles - 7y27 mentioned but not cited (1)

  1. Identification of a Novel SSTR3 Full Agonist for the Treatment of Nonfunctioning Pituitary Adenomas. Modena D, Moras ML, Sandrone G, Stevenazzi A, Vergani B, Dasgupta P, Kliever A, Gulde S, Marangelo A, Schillmaier M, Luque RM, Bäuerle S, Pellegata NS, Schulz S, Steinkühler C. Cancers (Basel) 15 3453 (2023)


Reviews citing this publication (1)

  1. Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands. Shpakov AO. Int J Mol Sci 24 6187 (2023)

Articles citing this publication (3)

  1. Interaction of Radiopharmaceuticals with Somatostatin Receptor 2 Revealed by Molecular Dynamics Simulations. Gervasoni S, Öztürk I, Guccione C, Bosin A, Ruggerone P, Malloci G. J Chem Inf Model 63 4924-4933 (2023)
  2. Molecular simulations of SSTR2 dynamics and interaction with ligands. Gervasoni S, Guccione C, Fanti V, Bosin A, Cappellini G, Golosio B, Ruggerone P, Malloci G. Sci Rep 13 4768 (2023)
  3. Structural basis of hydroxycarboxylic acid receptor signaling mechanisms through ligand binding. Suzuki S, Tanaka K, Nishikawa K, Suzuki H, Oshima A, Fujiyoshi Y. Nat Commun 14 5899 (2023)


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