8ZBE

cryo-EM structure of the octreotide-bound SSTR5-Gi complex

Summary for 8ZBE

• Entry DOI: 10.2210/pdb8zbe/pdb
• EMDB information: 39901
• Descriptor: Beta-2 adrenergic receptor,Somatostatin receptor type 5,lgbit (fusion protein), Guanine nucleotide-binding protein G(i) subunit alpha-1, Guanine nucleotide-binding protein subunit gamma, ... (6 entities in total)
• Functional Keywords: sstr5, octreoitde, structural protein, membrane protein/immune system, membrane protein-immune system complex
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 185122.72

Authors

Li, Y.G.,Meng, X.Y.,Yang, X.R.,Ling, S.L.,Shi, P.,Tian, C.L.,Yang, F. (deposition date: 2024-04-26, release date: 2024-07-10, Last modification date: 2024-11-13)

Primary citation

Li, Y.G.,Meng, X.Y.,Yang, X.,Ling, S.L.,Shi, P.,Tian, C.L.,Yang, F.
Structural insights into somatostatin receptor 5 bound with cyclic peptides.
Acta Pharmacol.Sin., 45:2432-2440, 2024

PubMed Abstract: Somatostatin receptor 5 (SSTR5) is highly expressed in ACTH-secreting pituitary adenomas and is an important drug target for the treatment of Cushing's disease. Two cyclic SST analog peptides (pasireotide and octreotide) both can activate SSTR5 and SSTR2. Pasireotide is preferential binding to SSTR5 than octreotide, while octreotide is biased to SSTR2 than SSTR5. The lack of selectivity of both pasireotide and octreotide causes side effects, such as hyperglycemia, gastrointestinal disturbance, and abnormal glucose homeostasis. However, little is known about the binding and selectivity mechanisms of pasireotide and octreotide with SSTR5, limiting the development of subtype-selective SST analog drugs specifically targeting SSTR5. Here, we report two cryo-electron microscopy (cryo-EM) structures of SSTR5-Gi complexes activated by pasireotide and octreoitde at resolutions of 3.09 Å and 3.24 Å, respectively. In combination with structural analysis and functional experiments, our results reveal the molecular mechanisms of ligand recognition and receptor activation. We also demonstrate that pasireotide preferentially binds to SSTR5 through the interactions between Tyr(Bzl)/Trp of pasireotide and SSTR5. Moreover, we find that the Q, N, F and ECL2 of SSTR2 play a crucial role in octreotide biased binding of SSTR2. Our results will provide structural insights and offer new opportunities for the drug discovery of better selective pharmaceuticals targeting specific SSTR subtypes.

PubMed: 38926478
DOI: 10.1038/s41401-024-01314-8

Experimental method

ELECTRON MICROSCOPY (3.24 Å)