Cryo-EM structure of the human somatostatin receptor 2 complex with its agonist somatostatin delineates the ligand binding specificity
- Yonsei University, Republic of Korea
- Korea Advanced Institute of Science and Technology, Republic of Korea
- Yokohama City University, Japan
- 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.
Article and author information
Author details
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
- Andrew C Kruse, Harvard Medical School, United States
Publication history
- Preprint posted: January 5, 2022 (view preprint)
- Received: January 6, 2022
- Accepted: April 20, 2022
- Accepted Manuscript published: April 21, 2022 (version 1)
- Version of Record published: April 29, 2022 (version 2)
- 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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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
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