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TitleStructural insights into somatostatin receptor 5 bound with cyclic peptides.
Journal, issue, pagesActa Pharmacol Sin, Year 2024
Publish dateJun 26, 2024
AuthorsYing-Ge Li / Xian-Yu Meng / Xiru Yang / Sheng-Long Ling / Pan Shi / Chang-Lin Tian / Fan Yang /
PubMed AbstractSomatostatin 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 ...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.
External linksActa Pharmacol Sin / PubMed:38926478
MethodsEM (single particle)
Resolution3.09 - 3.24 Å
Structure data

39901
EMDB entry, No image

8zbe

EMDB-39901, PDB-8zbe:
cryo-EM structure of the octreotide-bound SSTR5-Gi complex
Method: EM (single particle) / Resolution: 3.24 Å

39931
EMDB entry, No image

8zcj

EMDB-39931, PDB-8zcj:
Cryo-EM structure of the pasireotide-bound SSTR5-Gi complex
Method: EM (single particle) / Resolution: 3.09 Å

Source
  • homo sapiens (human)
  • oplophorus gracilirostris (crustacean)
  • rattus norvegicus (Norway rat)
  • synthetic construct (others)
  • bos taurus (cattle)
KeywordsMEMBRANE PROTEIN/IMMUNE SYSTEM / SSTR5 / octreoitde / structural protein / MEMBRANE PROTEIN-IMMUNE SYSTEM complex / pasireotide / Cryo-EM

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