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

Yunseok Heo, Eojin Yoon, Ye Eun Jeon, Ji Hye Yun, Naito Ishimoto, Hyeonuk Woo, Sam Yong Park, Ji Joon Song, Weontae Lee

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3 Citations (Scopus)


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 (Gi) 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.

Original languageEnglish
Article numbere76823
Publication statusPublished - 2022 Apr

Bibliographical note

Funding Information:
We thank the members of the Song and Lee Laboratories for technical assistance and helpful discussion. We also thank Dr Seung-Hee Lee for critical reading of this manuscript. We thank the staff of the cryo-EM facility at RIKEN Center for Biosystems Dynamics Research, Yokohama, Japan, and Korea Basic Science Institute (KBS), Daejeon, Korea, for the data collection. This work was supported by a grant (NRF-2020M3A9G7103934 to JS and WL) from the National Research Foundation (NRF) of Korea. The software programs used for the processing were supported by SBGrid (https://www. The computing resource was supported by the Global Science Experimental Data Hub Center (GSDC), Korea Institute of Science and Technology Information (KISTI), and by the data analysis hub, Olaf in the Institute of Basic Sciences (IBS) Research Solution Center.

Publisher Copyright:
© Heo et al.

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)


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