Cryo-EM structure of the human somatostatin receptor 2 complex with its agonist somatostatin delineates the ligand-binding specificity
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Evaluation Summary:
This manuscript reports the cryoEM structure of somatostatin receptor 2 (SSTR2) bound to its agonist SST-14 and a heterotrimeric G protein. In addition to presenting the structure itself, the authors include discussion and analysis of ligand recognition and subtype specificity, guided by AlphaFold2 modeling of other somatostatin receptor subtypes. Additional functional data to test the importance of proposed receptor-ligand contacts will be critical to understanding which of the features directly contribute to subtype specificity. Because somatostatin signaling is important in endocrine biology, including in diseases such as acromegaly and some cancers, the work should in principle be of interest to a broad audience.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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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 i ) 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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Evaluation Summary:
This manuscript reports the cryoEM structure of somatostatin receptor 2 (SSTR2) bound to its agonist SST-14 and a heterotrimeric G protein. In addition to presenting the structure itself, the authors include discussion and analysis of ligand recognition and subtype specificity, guided by AlphaFold2 modeling of other somatostatin receptor subtypes. Additional functional data to test the importance of proposed receptor-ligand contacts will be critical to understanding which of the features directly contribute to subtype specificity. Because somatostatin signaling is important in endocrine biology, including in diseases such as acromegaly and some cancers, the work should in principle be of interest to a broad audience.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the …
Evaluation Summary:
This manuscript reports the cryoEM structure of somatostatin receptor 2 (SSTR2) bound to its agonist SST-14 and a heterotrimeric G protein. In addition to presenting the structure itself, the authors include discussion and analysis of ligand recognition and subtype specificity, guided by AlphaFold2 modeling of other somatostatin receptor subtypes. Additional functional data to test the importance of proposed receptor-ligand contacts will be critical to understanding which of the features directly contribute to subtype specificity. Because somatostatin signaling is important in endocrine biology, including in diseases such as acromegaly and some cancers, the work should in principle be of interest to a broad audience.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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Reviewer #1 (Public Review):
The manuscript by Heo et al. describes the cryoEM structure of the somatostatin receptor 2 (SSTR2) bound to its agonist SST-14 and a heterotrimeric G protein. Somatostatin receptors are biologically important, with roles in acromegaly and a variety of other diseases. The structure of one of these receptors is therefore significant and likely to be of interest to a number of researchers. The manuscript is a bit disappointing in that it is purely descriptive, with no functional experiments to test proposed ideas around ligand recognition and specificity. At a minimum, It would be helpful to see site-directed mutagenesis to test the importance of specific contacts identified in the structure (accompanied by binding assays or signaling, with appropriate controls for differences in expression level). This would …
Reviewer #1 (Public Review):
The manuscript by Heo et al. describes the cryoEM structure of the somatostatin receptor 2 (SSTR2) bound to its agonist SST-14 and a heterotrimeric G protein. Somatostatin receptors are biologically important, with roles in acromegaly and a variety of other diseases. The structure of one of these receptors is therefore significant and likely to be of interest to a number of researchers. The manuscript is a bit disappointing in that it is purely descriptive, with no functional experiments to test proposed ideas around ligand recognition and specificity. At a minimum, It would be helpful to see site-directed mutagenesis to test the importance of specific contacts identified in the structure (accompanied by binding assays or signaling, with appropriate controls for differences in expression level). This would significantly improve the manuscript and the breadth of its appeal.
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Reviewer #2 (Public Review):
- A summary of what the authors were trying to achieve.
In this study the authors aimed at providing structural insights into how somatostatin binds to the type 2 receptor. This peptide hormone is having key role in regulating the endocrine systems so those structural studies are critical for drug development targeting SST receptors.
- An account of the major strengths and weaknesses of the methods and results.
The methodology to achieve their goal (biochemistry and CryoEM) is strong. The weaknesses are more related to how the authors put this work into the pharmacological context of SST receptor family and the discussion around the ligand-specific binding to SSTR2.
- An appraisal of whether the authors achieved their aims, and whether the results support their conclusions.
The authors definitely achieved …
Reviewer #2 (Public Review):
- A summary of what the authors were trying to achieve.
In this study the authors aimed at providing structural insights into how somatostatin binds to the type 2 receptor. This peptide hormone is having key role in regulating the endocrine systems so those structural studies are critical for drug development targeting SST receptors.
- An account of the major strengths and weaknesses of the methods and results.
The methodology to achieve their goal (biochemistry and CryoEM) is strong. The weaknesses are more related to how the authors put this work into the pharmacological context of SST receptor family and the discussion around the ligand-specific binding to SSTR2.
- An appraisal of whether the authors achieved their aims, and whether the results support their conclusions.
The authors definitely achieved their aims and their study provides important structural information regarding the binding of endogenous agonist, the activation of the SSTR 2 and its G protein coupling. Again, this is just a matter of how to discuss the structural data and to highlight the most relevant structural features for the fundamental aspect of GPCR function and for the SSTR2 pharmacology (and drug discovery).
- A discussion of the likely impact of the work on the field, and the utility of the methods and data to the community.
The study will likely impact on the field of GPCR structural biology and somatostatin pharmacology.
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