Conformational Transitions of the Pituitary Adenylate Cyclase-Activating Polypeptide Receptor, a Human Class B GPCR
Abstract The G protein-coupled pituitary adenylate cyclase-activating polypeptide receptor (PAC1R) is a potential therapeutic target for endocrine, metabolic and stress-related disorders. However, many questions regarding the protein structure and dynamics of PAC1R remain largely unanswered. Using m...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2017-07-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-017-05815-x |
| _version_ | 1818749250224259072 |
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| author | Chenyi Liao Xiaochuan Zhao Matthias Brewer Victor May Jianing Li |
| author_facet | Chenyi Liao Xiaochuan Zhao Matthias Brewer Victor May Jianing Li |
| author_sort | Chenyi Liao |
| collection | DOAJ |
| description | Abstract The G protein-coupled pituitary adenylate cyclase-activating polypeptide receptor (PAC1R) is a potential therapeutic target for endocrine, metabolic and stress-related disorders. However, many questions regarding the protein structure and dynamics of PAC1R remain largely unanswered. Using microsecond-long simulations, we examined the open and closed PAC1R conformations interconnected within an ensemble of transitional states. The open-to-closed transition can be initiated by “unzipping” the extracellular domain and the transmembrane domain, mediated by a unique segment within the β3-β4 loop. Transitions between different conformational states range between microseconds to milliseconds, which clearly implicate allosteric effects propagating from the extracellular face of the receptor to the intracellular G protein-binding site. Such allosteric dynamics provides structural and mechanistic insights for the activation and modulation of PAC1R and related class B receptors. |
| first_indexed | 2024-12-18T04:00:47Z |
| format | Article |
| id | doaj.art-a346ec78510746d69585d21cdea38cc6 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-18T04:00:47Z |
| publishDate | 2017-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-a346ec78510746d69585d21cdea38cc62022-12-21T21:21:41ZengNature PortfolioScientific Reports2045-23222017-07-01711710.1038/s41598-017-05815-xConformational Transitions of the Pituitary Adenylate Cyclase-Activating Polypeptide Receptor, a Human Class B GPCRChenyi Liao0Xiaochuan Zhao1Matthias Brewer2Victor May3Jianing Li4Department of Chemistry, University of VermontDepartment of Chemistry, University of VermontDepartment of Chemistry, University of VermontDepartment of Neurological Sciences, College of Medicine, University of VermontDepartment of Chemistry, University of VermontAbstract The G protein-coupled pituitary adenylate cyclase-activating polypeptide receptor (PAC1R) is a potential therapeutic target for endocrine, metabolic and stress-related disorders. However, many questions regarding the protein structure and dynamics of PAC1R remain largely unanswered. Using microsecond-long simulations, we examined the open and closed PAC1R conformations interconnected within an ensemble of transitional states. The open-to-closed transition can be initiated by “unzipping” the extracellular domain and the transmembrane domain, mediated by a unique segment within the β3-β4 loop. Transitions between different conformational states range between microseconds to milliseconds, which clearly implicate allosteric effects propagating from the extracellular face of the receptor to the intracellular G protein-binding site. Such allosteric dynamics provides structural and mechanistic insights for the activation and modulation of PAC1R and related class B receptors.https://doi.org/10.1038/s41598-017-05815-x |
| spellingShingle | Chenyi Liao Xiaochuan Zhao Matthias Brewer Victor May Jianing Li Conformational Transitions of the Pituitary Adenylate Cyclase-Activating Polypeptide Receptor, a Human Class B GPCR Scientific Reports |
| title | Conformational Transitions of the Pituitary Adenylate Cyclase-Activating Polypeptide Receptor, a Human Class B GPCR |
| title_full | Conformational Transitions of the Pituitary Adenylate Cyclase-Activating Polypeptide Receptor, a Human Class B GPCR |
| title_fullStr | Conformational Transitions of the Pituitary Adenylate Cyclase-Activating Polypeptide Receptor, a Human Class B GPCR |
| title_full_unstemmed | Conformational Transitions of the Pituitary Adenylate Cyclase-Activating Polypeptide Receptor, a Human Class B GPCR |
| title_short | Conformational Transitions of the Pituitary Adenylate Cyclase-Activating Polypeptide Receptor, a Human Class B GPCR |
| title_sort | conformational transitions of the pituitary adenylate cyclase activating polypeptide receptor a human class b gpcr |
| url | https://doi.org/10.1038/s41598-017-05815-x |
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