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Structural insight to mutation effects uncover a common allosteric site in class C GPCRs
MOTIVATION: Class C G protein-coupled receptors (GPCRs) regulate important physiological functions and allosteric modulators binding to the transmembrane domain constitute an attractive and, due to a lack of structural insight, a virtually unexplored potential for therapeutics and the food industry....
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5408886/ https://www.ncbi.nlm.nih.gov/pubmed/28011766 http://dx.doi.org/10.1093/bioinformatics/btw784 |
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author | Harpsøe, Kasper Boesgaard, Michael W Munk, Christian Bräuner-Osborne, Hans Gloriam, David E |
author_facet | Harpsøe, Kasper Boesgaard, Michael W Munk, Christian Bräuner-Osborne, Hans Gloriam, David E |
author_sort | Harpsøe, Kasper |
collection | PubMed |
description | MOTIVATION: Class C G protein-coupled receptors (GPCRs) regulate important physiological functions and allosteric modulators binding to the transmembrane domain constitute an attractive and, due to a lack of structural insight, a virtually unexplored potential for therapeutics and the food industry. Combining pharmacological site-directed mutagenesis data with the recent class C GPCR experimental structures will provide a foundation for rational design of new therapeutics. RESULTS: We uncover one common site for both positive and negative modulators with different amino acid layouts that can be utilized to obtain selectivity. Additionally, we show a large potential for structure-based modulator design, especially for four orphan receptors with high similarity to the crystal structures. AVAILABILITY AND IMPLEMENTATION: All collated mutagenesis data is available in the GPCRdb mutation browser at http://gpcrdb.org/mutations/ and can be analyzed online or downloaded in excel format. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. |
format | Online Article Text |
id | pubmed-5408886 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-54088862017-05-03 Structural insight to mutation effects uncover a common allosteric site in class C GPCRs Harpsøe, Kasper Boesgaard, Michael W Munk, Christian Bräuner-Osborne, Hans Gloriam, David E Bioinformatics Discovery Notes MOTIVATION: Class C G protein-coupled receptors (GPCRs) regulate important physiological functions and allosteric modulators binding to the transmembrane domain constitute an attractive and, due to a lack of structural insight, a virtually unexplored potential for therapeutics and the food industry. Combining pharmacological site-directed mutagenesis data with the recent class C GPCR experimental structures will provide a foundation for rational design of new therapeutics. RESULTS: We uncover one common site for both positive and negative modulators with different amino acid layouts that can be utilized to obtain selectivity. Additionally, we show a large potential for structure-based modulator design, especially for four orphan receptors with high similarity to the crystal structures. AVAILABILITY AND IMPLEMENTATION: All collated mutagenesis data is available in the GPCRdb mutation browser at http://gpcrdb.org/mutations/ and can be analyzed online or downloaded in excel format. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. Oxford University Press 2017-04-15 2016-12-22 /pmc/articles/PMC5408886/ /pubmed/28011766 http://dx.doi.org/10.1093/bioinformatics/btw784 Text en © The Author 2016. Published by Oxford University Press. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Discovery Notes Harpsøe, Kasper Boesgaard, Michael W Munk, Christian Bräuner-Osborne, Hans Gloriam, David E Structural insight to mutation effects uncover a common allosteric site in class C GPCRs |
title | Structural insight to mutation effects uncover a common allosteric site in class C GPCRs |
title_full | Structural insight to mutation effects uncover a common allosteric site in class C GPCRs |
title_fullStr | Structural insight to mutation effects uncover a common allosteric site in class C GPCRs |
title_full_unstemmed | Structural insight to mutation effects uncover a common allosteric site in class C GPCRs |
title_short | Structural insight to mutation effects uncover a common allosteric site in class C GPCRs |
title_sort | structural insight to mutation effects uncover a common allosteric site in class c gpcrs |
topic | Discovery Notes |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5408886/ https://www.ncbi.nlm.nih.gov/pubmed/28011766 http://dx.doi.org/10.1093/bioinformatics/btw784 |
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