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

doi:10.7554/eLife.76823

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

Research output: Contribution to journal › Article › peer-review

3 Citations (Scopus)

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.

Original language	English
Article number	e76823
Journal	eLife
Volume	11
DOIs	https://doi.org/10.7554/eLife.76823
Publication status	Published - 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. sbgrid.org/). 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)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.7554/eLife.76823

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

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.",

author = "Yunseok Heo and Eojin Yoon and Jeon, {Ye Eun} and Yun, {Ji Hye} and Naito Ishimoto and Hyeonuk Woo and Park, {Sam Yong} and Song, {Ji Joon} and Weontae Lee",

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. sbgrid.org/). 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: {\textcopyright} Heo et al.",

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doi = "10.7554/eLife.76823",

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AU - Heo, Yunseok

AU - Yoon, Eojin

AU - Jeon, Ye Eun

AU - Yun, Ji Hye

AU - Ishimoto, Naito

AU - Woo, Hyeonuk

AU - Park, Sam Yong

AU - Song, Ji Joon

AU - Lee, Weontae

N1 - 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. sbgrid.org/). 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.

PY - 2022/4

Y1 - 2022/4

N2 - 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.

AB - 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.

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

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

UN SDGs

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