7YAC

Paltusotine-bound SSTR2-Gi complex

Summary for 7YAC

• Entry DOI: 10.2210/pdb7yac/pdb
• EMDB information: 33708
• Descriptor: 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)
• Functional Keywords: agonist, membrane protein, complex, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 152390.08

Authors

Zhao, J.,Shao, Z. (deposition date: 2022-06-27, release date: 2023-04-19, Last modification date: 2024-10-30)

Primary citation

Zhao, J.,Fu, H.,Yu, J.,Hong, W.,Tian, X.,Qi, J.,Sun, S.,Zhao, C.,Wu, C.,Xu, Z.,Cheng, L.,Chai, R.,Yan, W.,Wei, X.,Shao, Z.
Prospect of acromegaly therapy: molecular mechanism of clinical drugs octreotide and paltusotine.
Nat Commun, 14:962-962, 2023

PubMed Abstract: Somatostatin receptor 2 (SSTR2) is highly expressed in neuroendocrine tumors and represents as a therapeutic target. Several peptide analogs mimicking the endogenous ligand somatostatin are available for clinical use, but poor therapeutic effects occur in a subset of patients, which may be correlated with subtype selectivity or cell surface expression. Here, we clarify the signal bias profiles of the first-generation peptide drug octreotide and a new-generation small molecule paltusotine by evaluating their pharmacological characteristics. We then perform cryo-electron microscopy analysis of SSTR2-Gi complexes to determine how the drugs activate SSTR2 in a selective manner. In this work, we decipher the mechanism of ligand recognition, subtype selectivity and signal bias property of SSTR2 sensing octreotide and paltusotine, which may aid in designing therapeutic drugs with specific pharmacological profiles against neuroendocrine tumors.

PubMed: 36810324
DOI: 10.1038/s41467-023-36673-z

Experimental method

ELECTRON MICROSCOPY (3.24 Å)