8ZCJ

Cryo-EM structure of the pasireotide-bound SSTR5-Gi complex

8ZCJ の概要

• エントリーDOI: 10.2210/pdb8zcj/pdb
• EMDBエントリー: 39931
• 分子名称: Guanine nucleotide-binding protein G(i) subunit alpha-1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• 機能のキーワード: pasireotide, sstr5, cryo-em, membrane protein/immune system, membrane protein-immune system complex
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 184976.49

構造登録者

Li, Y.G.,Meng, X.Y.,Yang, X.R.,Ling, S.L.,Shi, P.,Tian, C.L.,Yang, F. (登録日: 2024-04-29, 公開日: 2024-07-10, 最終更新日: 2024-10-30)

主引用文献

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

実験手法

ELECTRON MICROSCOPY (3.09 Å)