Unifying view of mechanical and functional hotspots across class A GPCRs.
G protein-coupled receptors (GPCRs) are the largest superfamily of signaling proteins. Their activation process is accompanied by conformational changes that have not yet been fully uncovered. Here, we carry out a novel comparative analysis of internal structural fluctuations across a variety of rec...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2017-02-01
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| Series: | PLoS Computational Biology |
| Online Access: | https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1005381&type=printable |
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| author | Luca Ponzoni Giulia Rossetti Luca Maggi Alejandro Giorgetti Paolo Carloni Cristian Micheletti |
| author_facet | Luca Ponzoni Giulia Rossetti Luca Maggi Alejandro Giorgetti Paolo Carloni Cristian Micheletti |
| author_sort | Luca Ponzoni |
| collection | DOAJ |
| description | G protein-coupled receptors (GPCRs) are the largest superfamily of signaling proteins. Their activation process is accompanied by conformational changes that have not yet been fully uncovered. Here, we carry out a novel comparative analysis of internal structural fluctuations across a variety of receptors from class A GPCRs, which currently has the richest structural coverage. We infer the local mechanical couplings underpinning the receptors' functional dynamics and finally identify those amino acids whose virtual deletion causes a significant softening of the mechanical network. The relevance of these amino acids is demonstrated by their overlap with those known to be crucial for GPCR function, based on static structural criteria. The differences with the latter set allow us to identify those sites whose functional role is more clearly detected by considering dynamical and mechanical properties. Of these sites with a genuine mechanical/dynamical character, the top ranking is amino acid 7x52, a previously unexplored, and experimentally verifiable key site for GPCR conformational response to ligand binding. |
| format | Article |
| id | doaj-art-bcbd196f5408458a8c03a2fa29b86b29 |
| institution | DOAJ |
| issn | 1553-734X 1553-7358 |
| language | English |
| publishDate | 2017-02-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Computational Biology |
| spelling | doaj-art-bcbd196f5408458a8c03a2fa29b86b292025-08-20T02:46:00ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582017-02-01132e100538110.1371/journal.pcbi.1005381Unifying view of mechanical and functional hotspots across class A GPCRs.Luca PonzoniGiulia RossettiLuca MaggiAlejandro GiorgettiPaolo CarloniCristian MichelettiG protein-coupled receptors (GPCRs) are the largest superfamily of signaling proteins. Their activation process is accompanied by conformational changes that have not yet been fully uncovered. Here, we carry out a novel comparative analysis of internal structural fluctuations across a variety of receptors from class A GPCRs, which currently has the richest structural coverage. We infer the local mechanical couplings underpinning the receptors' functional dynamics and finally identify those amino acids whose virtual deletion causes a significant softening of the mechanical network. The relevance of these amino acids is demonstrated by their overlap with those known to be crucial for GPCR function, based on static structural criteria. The differences with the latter set allow us to identify those sites whose functional role is more clearly detected by considering dynamical and mechanical properties. Of these sites with a genuine mechanical/dynamical character, the top ranking is amino acid 7x52, a previously unexplored, and experimentally verifiable key site for GPCR conformational response to ligand binding.https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1005381&type=printable |
| spellingShingle | Luca Ponzoni Giulia Rossetti Luca Maggi Alejandro Giorgetti Paolo Carloni Cristian Micheletti Unifying view of mechanical and functional hotspots across class A GPCRs. PLoS Computational Biology |
| title | Unifying view of mechanical and functional hotspots across class A GPCRs. |
| title_full | Unifying view of mechanical and functional hotspots across class A GPCRs. |
| title_fullStr | Unifying view of mechanical and functional hotspots across class A GPCRs. |
| title_full_unstemmed | Unifying view of mechanical and functional hotspots across class A GPCRs. |
| title_short | Unifying view of mechanical and functional hotspots across class A GPCRs. |
| title_sort | unifying view of mechanical and functional hotspots across class a gpcrs |
| url | https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1005381&type=printable |
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