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Cholesterol-dependent Conformational Plasticity in GPCR Dimers
The organization and function of the serotonin(1A) receptor, an important member of the GPCR family, have been shown to be cholesterol-dependent, although the molecular mechanism is not clear. We performed a comprehensive structural and dynamic analysis of dimerization of the serotonin(1A) receptor...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4989139/ https://www.ncbi.nlm.nih.gov/pubmed/27535203 http://dx.doi.org/10.1038/srep31858 |
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author | Prasanna, Xavier Sengupta, Durba Chattopadhyay, Amitabha |
author_facet | Prasanna, Xavier Sengupta, Durba Chattopadhyay, Amitabha |
author_sort | Prasanna, Xavier |
collection | PubMed |
description | The organization and function of the serotonin(1A) receptor, an important member of the GPCR family, have been shown to be cholesterol-dependent, although the molecular mechanism is not clear. We performed a comprehensive structural and dynamic analysis of dimerization of the serotonin(1A) receptor by coarse-grain molecular dynamics simulations totaling 3.6 ms to explore the molecular details of its cholesterol-dependent association. A major finding is that the plasticity and flexibility of the receptor dimers increase with increased cholesterol concentration. In particular, a dimer interface formed by transmembrane helices I-I was found to be sensitive to cholesterol. The modulation of dimer interface appears to arise from a combination of direct cholesterol occupancy and indirect membrane effects. Interestingly, the presence of cholesterol at the dimer interface is correlated with increased dimer plasticity and flexibility. These results represent an important step in characterizing the molecular interactions in GPCR organization with potential relevance to therapeutic interventions. |
format | Online Article Text |
id | pubmed-4989139 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-49891392016-08-30 Cholesterol-dependent Conformational Plasticity in GPCR Dimers Prasanna, Xavier Sengupta, Durba Chattopadhyay, Amitabha Sci Rep Article The organization and function of the serotonin(1A) receptor, an important member of the GPCR family, have been shown to be cholesterol-dependent, although the molecular mechanism is not clear. We performed a comprehensive structural and dynamic analysis of dimerization of the serotonin(1A) receptor by coarse-grain molecular dynamics simulations totaling 3.6 ms to explore the molecular details of its cholesterol-dependent association. A major finding is that the plasticity and flexibility of the receptor dimers increase with increased cholesterol concentration. In particular, a dimer interface formed by transmembrane helices I-I was found to be sensitive to cholesterol. The modulation of dimer interface appears to arise from a combination of direct cholesterol occupancy and indirect membrane effects. Interestingly, the presence of cholesterol at the dimer interface is correlated with increased dimer plasticity and flexibility. These results represent an important step in characterizing the molecular interactions in GPCR organization with potential relevance to therapeutic interventions. Nature Publishing Group 2016-08-18 /pmc/articles/PMC4989139/ /pubmed/27535203 http://dx.doi.org/10.1038/srep31858 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Prasanna, Xavier Sengupta, Durba Chattopadhyay, Amitabha Cholesterol-dependent Conformational Plasticity in GPCR Dimers |
title | Cholesterol-dependent Conformational Plasticity in GPCR Dimers |
title_full | Cholesterol-dependent Conformational Plasticity in GPCR Dimers |
title_fullStr | Cholesterol-dependent Conformational Plasticity in GPCR Dimers |
title_full_unstemmed | Cholesterol-dependent Conformational Plasticity in GPCR Dimers |
title_short | Cholesterol-dependent Conformational Plasticity in GPCR Dimers |
title_sort | cholesterol-dependent conformational plasticity in gpcr dimers |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4989139/ https://www.ncbi.nlm.nih.gov/pubmed/27535203 http://dx.doi.org/10.1038/srep31858 |
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