8X8L

Cryo-EM structure of the cortistatin 17-bound Somatostatin receptor 5-Gi protein complex

Summary for 8X8L

• Entry DOI: 10.2210/pdb8x8l/pdb
• EMDB information: 38148
• Descriptor: Guanine nucleotide-binding protein G(i) subunit alpha, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Cortistatin, ... (6 entities in total)
• Functional Keywords: cryo-em, gpcr, somatostatin receptor 5, cortistatin 17, gi, complex, signaling protein
• Biological source: Homo sapiens; More
• Total number of polymer chains: 6
• Total formula weight: 157354.21

Authors

Xu, H.E.,You, C.,Zhao, L.,Li, J. (deposition date: 2023-11-27, release date: 2024-06-12, Last modification date: 2024-12-25)

Primary citation

Li, J.,You, C.,Li, Y.,Li, C.,Fan, W.,Chen, Z.,Hu, W.,Wu, K.,Xu, H.E.,Zhao, L.H.
Structural basis for activation of somatostatin receptor 5 by cyclic neuropeptide agonists.
Proc.Natl.Acad.Sci.USA, 121:e2321710121-e2321710121, 2024

PubMed Abstract: Somatostatin receptor 5 (SSTR5) is an important G protein-coupled receptor and drug target for neuroendocrine tumors and pituitary disorders. This study presents two high-resolution cryogenicelectron microscope structures of the SSTR5-G complexes bound to the cyclic neuropeptide agonists, cortistatin-17 (CST17) and octreotide, with resolutions of 2.7 Å and 2.9 Å, respectively. The structures reveal that binding of these peptides causes rearrangement of a "hydrophobic lock", consisting of residues from transmembrane helices TM3 and TM6. This rearrangement triggers outward movement of TM6, enabling Gα protein engagement and receptor activation. In addition to hydrophobic interactions, CST17 forms conserved polar contacts similar to somatostatin-14 binding to SSTR2, while further structural and functional analysis shows that extracellular loops differently recognize CST17 and octreotide. These insights elucidate agonist selectivity and activation mechanisms of SSTR5, providing valuable guidance for structure-based drug development targeting this therapeutically relevant receptor.

PubMed: 38885377
DOI: 10.1073/pnas.2321710121

Experimental method

ELECTRON MICROSCOPY (2.7 Å)