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

  1. Yunseok Heo
  2. Eojin Yoon
  3. Ye-Eun Jeon
  4. Ji-Hye Yun
  5. Naito Ishimoto
  6. Hyeonuk Woo
  7. Sam-Yong Park
  8. Ji-Joon Song  Is a corresponding author
  9. Weontae Lee  Is a corresponding author
  1. Yonsei University, Republic of Korea
  2. Korea Advanced Institute of Science and Technology, Republic of Korea
  3. Yokohama City University, Japan
  4. Seoul National University, Republic of Korea

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 (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.

Data availability

The cryo-EM map and the model are to be deposited at EMDB (www.ebi.ac.uk) and RCSB (www.rcsb.org) data base with the accession codes of EMD-32543 and 7WJ5, respectively.

The following data sets were generated

Article and author information

Author details

  1. Yunseok Heo

    Department of Biochemistry, Yonsei University, Seoul, Republic of Korea
    Competing interests
    No competing interests declared.
  2. Eojin Yoon

    Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
    Competing interests
    No competing interests declared.
  3. Ye-Eun Jeon

    Department of Biochemistry, Yonsei University, Seoul, Republic of Korea
    Competing interests
    No competing interests declared.
  4. Ji-Hye Yun

    Department of Biochemistry, Yonsei University, Seoul, Republic of Korea
    Competing interests
    Ji-Hye Yun, is an employee at PCG-Biotech and holds a research director position..
  5. Naito Ishimoto

    Drug Design Laboratory, Yokohama City University, Yokohama, Japan
    Competing interests
    No competing interests declared.
  6. Hyeonuk Woo

    Department of Chemistry, Seoul National University, Seoul, Republic of Korea
    Competing interests
    No competing interests declared.
  7. Sam-Yong Park

    Drug Design Laboratory, Yokohama City University, Yokohama, Japan
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6164-8896
  8. Ji-Joon Song

    Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
    For correspondence
    songj@kaist.ac.kr
    Competing interests
    Ji-Joon Song, is a co-founder of PCG-Biotech.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7120-6311
  9. Weontae Lee

    Department of Biochemistry, Yonsei University, Seoul, Republic of Korea
    For correspondence
    wlee@spin.yonsei.ac.kr
    Competing interests
    Weontae Lee, is a co-founder of PCG-Biotech.

Funding

National Research Foundation of Korea (NRF-2020M3A9G7103934)

  • Ji-Joon Song

National Research Foundation of Korea (NRF-2020M3A9G7103934)

  • Weontae Lee

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Andrew C Kruse, Harvard Medical School, United States

Version history

  1. Preprint posted: January 5, 2022 (view preprint)
  2. Received: January 6, 2022
  3. Accepted: April 20, 2022
  4. Accepted Manuscript published: April 21, 2022 (version 1)
  5. Version of Record published: April 29, 2022 (version 2)
  6. Version of Record updated: June 8, 2022 (version 3)

Copyright

© 2022, Heo et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Yunseok Heo
  2. Eojin Yoon
  3. Ye-Eun Jeon
  4. Ji-Hye Yun
  5. Naito Ishimoto
  6. Hyeonuk Woo
  7. Sam-Yong Park
  8. Ji-Joon Song
  9. Weontae Lee
(2022)
Cryo-EM structure of the human somatostatin receptor 2 complex with its agonist somatostatin delineates the ligand binding specificity
eLife 11:e76823.
https://doi.org/10.7554/eLife.76823

Share this article

https://doi.org/10.7554/eLife.76823

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