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Exploration of Somatostatin Binding Mechanism to Somatostatin Receptor Subtype 4

Somatostatin (also named as growth hormone-inhibiting hormone or somatotropin release-inhibiting factor) is a regulatory peptide important for the proper functioning of the endocrine system, local inflammatory reactions, mood and motor coordination, and behavioral responses to stress. Somatostatin e...

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Autores principales: Börzsei, Rita, Zsidó, Balázs Zoltán, Bálint, Mónika, Helyes, Zsuzsanna, Pintér, Erika, Hetényi, Csaba
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9266823/
https://www.ncbi.nlm.nih.gov/pubmed/35805885
http://dx.doi.org/10.3390/ijms23136878
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author Börzsei, Rita
Zsidó, Balázs Zoltán
Bálint, Mónika
Helyes, Zsuzsanna
Pintér, Erika
Hetényi, Csaba
author_facet Börzsei, Rita
Zsidó, Balázs Zoltán
Bálint, Mónika
Helyes, Zsuzsanna
Pintér, Erika
Hetényi, Csaba
author_sort Börzsei, Rita
collection PubMed
description Somatostatin (also named as growth hormone-inhibiting hormone or somatotropin release-inhibiting factor) is a regulatory peptide important for the proper functioning of the endocrine system, local inflammatory reactions, mood and motor coordination, and behavioral responses to stress. Somatostatin exerts its effects via binding to G-protein-coupled somatostatin receptors of which the fourth subtype (SSTR4) is a particularly important receptor mediating analgesic, anti-inflammatory, and anti-depressant effects without endocrine actions. Thus, SSTR4 agonists are promising drug candidates. Although the knowledge of the atomic resolution-binding modes of SST would be essential for drug development, experimental elucidation of the structures of SSTR4 and its complexes is still awaiting. In the present study, structures of the somatostatin–SSTR4 complex were produced using an unbiased, blind docking approach. Beyond the static structures, the binding mechanism of SST was also elucidated in the explicit water molecular dynamics (MD) calculations, and key binding modes (external, intermediate, and internal) were distinguished. The most important residues on both receptor and SST sides were identified. An energetic comparison of SST binding to SSTR4 and 2 offered a residue-level explanation of receptor subtype selectivity. The calculated structures show good agreement with available experimental results and indicate that somatostatin binding is realized via prerequisite binding modes and an induced fit mechanism. The identified binding modes and the corresponding key residues provide useful information for future drug design targeting SSTR4.
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spelling pubmed-92668232022-07-09 Exploration of Somatostatin Binding Mechanism to Somatostatin Receptor Subtype 4 Börzsei, Rita Zsidó, Balázs Zoltán Bálint, Mónika Helyes, Zsuzsanna Pintér, Erika Hetényi, Csaba Int J Mol Sci Article Somatostatin (also named as growth hormone-inhibiting hormone or somatotropin release-inhibiting factor) is a regulatory peptide important for the proper functioning of the endocrine system, local inflammatory reactions, mood and motor coordination, and behavioral responses to stress. Somatostatin exerts its effects via binding to G-protein-coupled somatostatin receptors of which the fourth subtype (SSTR4) is a particularly important receptor mediating analgesic, anti-inflammatory, and anti-depressant effects without endocrine actions. Thus, SSTR4 agonists are promising drug candidates. Although the knowledge of the atomic resolution-binding modes of SST would be essential for drug development, experimental elucidation of the structures of SSTR4 and its complexes is still awaiting. In the present study, structures of the somatostatin–SSTR4 complex were produced using an unbiased, blind docking approach. Beyond the static structures, the binding mechanism of SST was also elucidated in the explicit water molecular dynamics (MD) calculations, and key binding modes (external, intermediate, and internal) were distinguished. The most important residues on both receptor and SST sides were identified. An energetic comparison of SST binding to SSTR4 and 2 offered a residue-level explanation of receptor subtype selectivity. The calculated structures show good agreement with available experimental results and indicate that somatostatin binding is realized via prerequisite binding modes and an induced fit mechanism. The identified binding modes and the corresponding key residues provide useful information for future drug design targeting SSTR4. MDPI 2022-06-21 /pmc/articles/PMC9266823/ /pubmed/35805885 http://dx.doi.org/10.3390/ijms23136878 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Börzsei, Rita
Zsidó, Balázs Zoltán
Bálint, Mónika
Helyes, Zsuzsanna
Pintér, Erika
Hetényi, Csaba
Exploration of Somatostatin Binding Mechanism to Somatostatin Receptor Subtype 4
title Exploration of Somatostatin Binding Mechanism to Somatostatin Receptor Subtype 4
title_full Exploration of Somatostatin Binding Mechanism to Somatostatin Receptor Subtype 4
title_fullStr Exploration of Somatostatin Binding Mechanism to Somatostatin Receptor Subtype 4
title_full_unstemmed Exploration of Somatostatin Binding Mechanism to Somatostatin Receptor Subtype 4
title_short Exploration of Somatostatin Binding Mechanism to Somatostatin Receptor Subtype 4
title_sort exploration of somatostatin binding mechanism to somatostatin receptor subtype 4
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9266823/
https://www.ncbi.nlm.nih.gov/pubmed/35805885
http://dx.doi.org/10.3390/ijms23136878
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