7WJ5

Cryo-EM structure of human somatostatin receptor 2 complex with its agonist somatostatin delineates the ligand binding specificity

Summary for 7WJ5

• Entry DOI: 10.2210/pdb7wj5/pdb
• EMDB information: 32543
• Related PRD ID: PRD_001216
• 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: gpcr, agonist, heterotrimeric g-protein, camp, membrane protein, membrane protein-immune system complex, membrane protein/immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 176136.43

Authors

Heo, Y.S.,Yoon, E.J.,Jeon, Y.E.,Yun, J.-H.,Ishimoto, N.,Woo, H.,Park, S.Y.,Song, J.,Lee, W.T. (deposition date: 2022-01-05, release date: 2022-07-13, Last modification date: 2024-11-06)

Primary citation

Heo, Y.,Yoon, E.,Jeon, Y.E.,Yun, J.H.,Ishimoto, N.,Woo, H.,Park, S.Y.,Song, J.J.,Lee, W.
Cryo-EM structure of the human somatostatin receptor 2 complex with its agonist somatostatin delineates the ligand-binding specificity.
Elife, 11:-, 2022

PubMed Abstract: Somatostatin is a peptide hormone that regulates endocrine systems by binding to G-protein-coupled somatostatin receptors. Somatostatin receptor 2 (SSTR2) is a human somatostatin receptor and is highly implicated in hormone disorders, cancers, and neurological diseases. Here, we report the high-resolution cryo-EM structure of full-length human SSTR2 bound to the agonist somatostatin (SST-14) in complex with inhibitory G (G) proteins. Our structural and mutagenesis analyses show that seven transmembrane helices form a deep pocket for ligand binding and that SSTR2 recognizes the highly conserved Trp-Lys motif of SST-14 at the bottom of the pocket. Furthermore, our sequence analysis combined with AlphaFold modeled structures of other SSTR isoforms provide a structural basis for the mechanism by which SSTR family proteins specifically interact with their cognate ligands. This work provides the first glimpse into the molecular recognition mechanism of somatostatin receptors and a crucial resource to develop therapeutics targeting somatostatin receptors.

PubMed: 35446253
DOI: 10.7554/eLife.76823

Experimental method

ELECTRON MICROSCOPY (3.72 Å)