Mechanism of activation and biased signaling in complement receptor C5aR1

Feng, Yuying; Zhao, Chang; Deng, Yue; Ma, Liang; Liu, Sicen; Tian, Xiaowen; Wang, Bo; Yan, Binbin; Chen, Peipei; Yan, Wei; Fu, Ping; Shao, Zhenhua

doi:10.1038/s41422-023-00779-2

Cited by 24 publications

(38 citation statements)

References 68 publications

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“…It is evident from the binary and ternary complex (Figure 1) structures that the Helix2‐L 2 ‐Helix3‐L 3 region and the CT‐peptide region (I65–R74) of C5a are collectively involved in binding to the receptors. The cryo‐EM ternary complex data indicates that R74 of C5a interacts with D282 of C5aR1 6,7 . Moreover, C5a fails to trigger the activation of G‐protein through D282A and D282E mutants of C5aR1.…”

Section: Discussionmentioning

confidence: 96%

“…The cryo-EM ternary complex data indicates that R74 of C5a interacts with D282 of C5aR1. 6,7 Moreover, C5a fails to trigger the activation of G-protein through D282A and D282E mutants of C5aR1. Further, it is observed that R74 can form a "cation-π" interaction with Y258 of C5aR1.…”

Section: Estimating the Binding Free Energy Of The Antibody-like Pept...mentioning

confidence: 99%

“…C5a further propagates its proinflammatory action by binding to a pair of genomically related G‐protein coupled receptors like C5aR1 3 and C5aR2 4 . The bulk of C5a aids the initial recognition of the receptors, whereas the CT‐region is crucial for activation and the respective recruitment of G‐protein and β‐arrestin for generating the activated ternary signaling complex of C5aR1 5–7 and C5aR2 8…”

Section: Introductionmentioning

confidence: 99%

“…In its receptor‐free form, C5a has been described as a conformationally dynamic protein with a highly flexible L 2 ‐Helix3‐L 3 region and the CT‐region 9 . Both computational 10–12 and experimental 13,14 studies have evidenced that C5a undergoes further conformational changes in response to the binding of the N‐terminal (NT) region of the receptors, which further alters the conformation of the CT‐region of C5a, allowing it to dock into the interhelical crevices of the C5aR1/C5aR2 through conformational selection while establishing intermolecular contacts with the extracellular loop 2 (ECL2) of the receptors 6,7 . In a broad sense, in receptor‐bound form, the bulk and CT‐region of C5a collectively make two‐site contacts with the extracellular surface (ECS) of the receptors (Figure 1) through various electrostatic, hydrogen bonding, and hydrophobic interactions.…”

Section: Introductionmentioning

confidence: 99%

“…intermolecular contacts with the extracellular loop 2 (ECL2) of the receptors. 6,7 In a broad sense, in receptor-bound form, the bulk and CT-region of C5a collectively make two-site contacts with the extracellular surface (ECS) of the receptors (Figure 1) through various electrostatic, hydrogen bonding, and hydrophobic interactions. The importance of C5a's interaction with C5aR1 and C5aR2 has been clinically established, and overstimulation of the receptors by C5a is known to contribute significantly toward a variety of immuno-inflammatory pathophysiological conditions.…”

mentioning

confidence: 99%

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Rational design of antibody‐like peptides for targeting the human complement fragment protein C5a

Ghosh,

Shadangi,

Rana

2023

Proteins

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Human complement fragment 5a (C5a) is one of the most potent glycoproteins generated downstream of C3a and C4a during late‐stage activation of the complement signaling cascade. C5a recruits receptors like C5aR1 and C5aR2 and is established to play a critical role in complement‐mediated inflammation. Thus, excessive C5a in the plasma due to aberrant activation of the complement contributes to the pathophysiology of several chronic inflammatory diseases. Therefore, restricting the excessive interaction of C5a with its receptors by neutralizing C5a has been one of the most effective therapeutic strategies for the management of inflammatory diseases. Indeed, antibodies targeting C5 (Eculizumab), the precursor of C5a, and C5a (Vilobelimab) have already been approved by the FDA. Still, small designer peptides that work like antibodies and can target and stop C5a from interacting with its receptors seem to be a possible therapeutic alternative to antibodies because they are smaller, cheaper to make, more specific to their target, and can get through membrane barriers. As a proof‐of‐principle, the current study describes the computational design and evaluation of a pair of peptides that are able to form stable high‐affinity complexes with the epitope regions of C5a that are important for the recruitment of C5aR1 and C5aR2. The computational data further supports the potential of designer peptides for mimicking the function of antibodies targeting C5a. However, further experimental studies will be required to establish the structure–function relationship of the designer peptides and also to establish the hypothesis of antibody‐like peptides targeting C5a.

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Section: Discussionmentioning

confidence: 96%

Section: Estimating the Binding Free Energy Of The Antibody-like Pept...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Rational design of antibody‐like peptides for targeting the human complement fragment protein C5a

Ghosh,

Shadangi,

Rana

2023

Proteins

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Exploration of compounds to inhibit the Panton-Valentine leukocidin of Staphylococcus aureus

Grebe,

Sarkari,

Cherkaoui

et al. 2024

Med Microbiol Immunol

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The Panton-Valentine leukocidin (PVL) of Staphylococcus aureus is associated with necrotizing infections. After binding to complement 5a receptor (C5aR/CD88) and CD45 it causes cytolysis in polymorphonuclear neutrophils (PMNs) as well as inflammasome activation in monocytes. The objective of this study was to test if (ant)agonists of C5aR and CD45 can attenuate the effect of PVL on PMNs and monocytes. We tested the effect of various concentrations of six C5aR (ant)agonists (avacopan, BM213, DF2593A, JPE-1375, PMX205 and W-54011) and one CD45 antagonist (NQ301) to attenuate the cytotoxic effect of PVL on human PMNs and monocytes in vitro. Shifts in the half-maximal effective concentration (EC50) of PVL to achieve a cytotoxic effect on PMNs and modulation of inflammatory cytokine response from monocytes were determined by flow cytometry and IL-1β detection. Pre-treatment of PMNs with avacopan, PMX205 and W-54,011 resulted in 3.6- to 4.3-fold shifts in the EC50 for PVL and were able to suppress IL-1β secretion by human monocytes in the presence of PVL. BM213, DF2593A and NQ301 were unable to change the susceptibility of PMNs towards PVL or reduce inflammasome activation in monocytes. Avacopan, PMX205 and W-54,011 showed protection against PVL-induced cytotoxicity and suppressed IL-1β secretion by monocytes. Clinical studies are needed to prove whether these substances can be used therapeutically as repurposed drugs.

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Hematopoiesis Revolves Around the Primordial Evolutional Rhythm of Purinergic Signaling and Innate Immunity – A Journey to the Developmental Roots

Ratajczak,

Bujko,

Brzezniakiewicz-Janus

et al. 2024

Stem Cell Rev and Rep

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A cell's most significant existential task is to survive by ensuring proper metabolism, avoiding harmful stimuli, and adapting to changing environments. It explains why early evolutionary primordial signals and pathways remained active and regulate cell and tissue integrity. This requires energy supply and a balanced redox state. To meet these requirements, the universal intracellular energy transporter purine nucleotide-adenosine triphosphate (ATP) became an important signaling molecule and precursor of purinergic signaling after being released into extracellular space. Similarly, ancient proteins involved in intracellular metabolism gave rise to the third protein component (C3) of the complement cascade (ComC), a soluble arm of innate immunity. These pathways induce cytosol reactive oxygen (ROS) and reactive nitrogen species (RNS) that regulate the redox state of the cells. While low levels of ROS and RNS promote cell growth and differentiation, supra-physiological concentrations can lead to cell damage by pyroptosis. This balance explains the impact of purinergic signaling and innate immunity on cell metabolism, organogenesis, and tissue development. Subsequently, along with evolution, new regulatory cues emerge in the form of growth factors, cytokines, chemokines, and bioactive lipids. However, their expression is still modulated by both primordial signaling pathways. This review will focus on the data that purinergic signaling and innate immunity carry on their ancient developmental task in hematopoiesis and specification of hematopoietic stem/progenitor cells (HSPCs). Moreover, recent evidence shows both these regulatory pathways operate in a paracrine manner and inside HSPCs at the autocrine level. Graphical Abstract

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Mechanism of activation and biased signaling in complement receptor C5aR1

Cited by 24 publications

References 68 publications

Rational design of antibody‐like peptides for targeting the human complement fragment protein C5a

Rational design of antibody‐like peptides for targeting the human complement fragment protein C5a

Exploration of compounds to inhibit the Panton-Valentine leukocidin of Staphylococcus aureus

Hematopoiesis Revolves Around the Primordial Evolutional Rhythm of Purinergic Signaling and Innate Immunity – A Journey to the Developmental Roots

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