Helix 8 in chemotactic receptors of the complement system.
Host response to infection involves the activation of the complement system leading to the production of anaphylatoxins C3a and C5a. Complement factor C5a exerts its effect through the activation of C5aR1, chemotactic receptor 1, and triggers the G protein-coupled signaling cascade. Orthosteric and...
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Format: | Article |
Language: | English |
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Public Library of Science (PLoS)
2022-07-01
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Series: | PLoS Computational Biology |
Online Access: | https://doi.org/10.1371/journal.pcbi.1009994 |
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author | Szymon Wisniewski Paulina Dragan Anna Makal Dorota Latek |
author_facet | Szymon Wisniewski Paulina Dragan Anna Makal Dorota Latek |
author_sort | Szymon Wisniewski |
collection | DOAJ |
description | Host response to infection involves the activation of the complement system leading to the production of anaphylatoxins C3a and C5a. Complement factor C5a exerts its effect through the activation of C5aR1, chemotactic receptor 1, and triggers the G protein-coupled signaling cascade. Orthosteric and allosteric antagonists of C5aR1 are a novel strategy for anti-inflammatory therapies. Here, we discuss recent crystal structures of inactive C5aR1 in terms of an inverted orientation of helix H8, unobserved in other GPCR structures. An analysis of mutual interactions of subunits in the C5aR1-G protein complex has provided new insights into the activation mechanism of this distinct receptor. By comparing two C5aR receptors C5aR1 and C5aR2 we explained differences between their signaling pathways on the molecular level. By means of molecular dynamics we explained why C5aR2 cannot transduce signal through the G protein pathway but instead recruits beta-arrestin. A comparison of microsecond MD trajectories started from active and inactive C5aR1 receptor conformations has provided insights into details of local and global changes in the transmembrane domain induced by interactions with the Gα subunit and explained the impact of inverted H8 on the C5aR1 activation. |
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id | doaj.art-c5ccd9300d3e4b1dbbc87b85eb0bd37f |
institution | Directory Open Access Journal |
issn | 1553-734X 1553-7358 |
language | English |
last_indexed | 2024-04-12T06:07:34Z |
publishDate | 2022-07-01 |
publisher | Public Library of Science (PLoS) |
record_format | Article |
series | PLoS Computational Biology |
spelling | doaj.art-c5ccd9300d3e4b1dbbc87b85eb0bd37f2022-12-22T03:44:50ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582022-07-01187e100999410.1371/journal.pcbi.1009994Helix 8 in chemotactic receptors of the complement system.Szymon WisniewskiPaulina DraganAnna MakalDorota LatekHost response to infection involves the activation of the complement system leading to the production of anaphylatoxins C3a and C5a. Complement factor C5a exerts its effect through the activation of C5aR1, chemotactic receptor 1, and triggers the G protein-coupled signaling cascade. Orthosteric and allosteric antagonists of C5aR1 are a novel strategy for anti-inflammatory therapies. Here, we discuss recent crystal structures of inactive C5aR1 in terms of an inverted orientation of helix H8, unobserved in other GPCR structures. An analysis of mutual interactions of subunits in the C5aR1-G protein complex has provided new insights into the activation mechanism of this distinct receptor. By comparing two C5aR receptors C5aR1 and C5aR2 we explained differences between their signaling pathways on the molecular level. By means of molecular dynamics we explained why C5aR2 cannot transduce signal through the G protein pathway but instead recruits beta-arrestin. A comparison of microsecond MD trajectories started from active and inactive C5aR1 receptor conformations has provided insights into details of local and global changes in the transmembrane domain induced by interactions with the Gα subunit and explained the impact of inverted H8 on the C5aR1 activation.https://doi.org/10.1371/journal.pcbi.1009994 |
spellingShingle | Szymon Wisniewski Paulina Dragan Anna Makal Dorota Latek Helix 8 in chemotactic receptors of the complement system. PLoS Computational Biology |
title | Helix 8 in chemotactic receptors of the complement system. |
title_full | Helix 8 in chemotactic receptors of the complement system. |
title_fullStr | Helix 8 in chemotactic receptors of the complement system. |
title_full_unstemmed | Helix 8 in chemotactic receptors of the complement system. |
title_short | Helix 8 in chemotactic receptors of the complement system. |
title_sort | helix 8 in chemotactic receptors of the complement system |
url | https://doi.org/10.1371/journal.pcbi.1009994 |
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