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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Main Authors: Szymon Wisniewski, Paulina Dragan, Anna Makal, Dorota Latek
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2022-07-01
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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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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AT annamakal helix8inchemotacticreceptorsofthecomplementsystem
AT dorotalatek helix8inchemotacticreceptorsofthecomplementsystem