Orthosteric and allosteric action of the C5a receptor antagonists

Liu, Heng; Kim, Hee Ryung; Deepak, R. N. V. Krishna; Wang, Lei; Chung, Ka Young; Fan, Hao; Wei, Zhiyi; Zhang, Cheng

doi:10.1038/s41594-018-0067-z

Cited by 115 publications

(158 citation statements)

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“…Our findings also suggest that a more comprehensive analysis of C5a fragments might yield βarr-biased ligands at C5aR1. Although crystal structures of C5aR1 bound to small molecule antagonists have been determined recently (22,23), C5a-bound structure is still not available. High-resolution structure details of C5a-bound C5aR1 in future may provide structural insights into differential engagement of C5a pep compared to C5a and how these differential interactions in the ligand-binding pocket yield transducer-coupling bias.…”

Section: Resultsmentioning

confidence: 99%

Partial ligand-receptor engagement yields functional bias at the human complement receptor, C5aR1

Pandey¹,

Srivastava³

et al. 2019

Preprint

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20The human complement component, C5a, binds two different seven transmembrane receptors termed 21 as C5aR1 and C5aR2. C5aR1 is a prototypical G protein-coupled receptor that couples to Gαi sub-family 22 of heterotrimeric G proteins and β-arrestins (βarr) following C5a stimulation. Peptide fragments derived 23 from the carboxyl-terminus of C5a can still interact with the receptor, albeit with lower affinity, and can 24 act as agonists or antagonists. However, whether such fragments might display ligand bias at C5aR1 25 remains unexplored. Here, we compare C5a and a modified C-terminal fragment of C5a, C5a pep , in terms 26 of G protein coupling, βarr recruitment, endocytosis and ERK1/2 MAP kinase activation at the human 27C5aR1. We discover that C5a pep acts as a full-agonist for G protein coupling, while only displaying partial 28 agonism for βarr recruitment. We also observe that whilst C5a pep is significantly less efficient in inducing 29

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Section: Resultsmentioning

confidence: 99%

Partial ligand-receptor engagement yields functional bias at the human complement receptor, C5aR1

Pandey¹,

Srivastava³

et al. 2019

Preprint

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“…The height of the emergent part of C5aR above the lipid bilayer (protrusion height) as well as its diameter (calculated as the full width at half maximum) were extracted for each particle and plotted in a two-dimensional histogram (2D) ( Figures 1D and E ). A bimodal distribution is observed for the heights, with two peaks centered respectively at 1.1 ± 0.5 nm and 2.8 ± 1.2 nm, while the presence of three main populations can be observed for the diameters, with peaks centered at 8.6 ± 0.4 nm (monomers), 14.1 ± 0.3 nm (dimers) and 23.4 ± 1.2 nm (oligomers) (László, Miklós et al , 2008; Alsteens, Pfreundschuh et al , 2015; Liu, Kim et al , 2018). The two peaks of height distribution could represent the heights of the extracellular and the intracellular regions of C5aR protruding from the DOPC/CHS membrane.…”

Section: Resultsmentioning

confidence: 99%

“…To better investigate the key residues responsible for the high affinity interaction, we turned our attention to PMX53, a well-known C5aR full antagonist that mimics the structure of the C-terminal segment of C5a (March, Proctor et al , 2004; Monk, Scola et al , 2007; Woodruff, Nandakumar et al , 2011). The C5aR-PMX53 crystal structure (Liu, Kim et al , 2018) has been recently elucidated and we can hypothesize that given their high structural similarities, the cyclic hexapeptide PMX53 and the C-terminal segment interact with C5aR through similar residues. To get more insight into the PMX53-C5aR binding dynamics we performed molecular dynamics (MD) and steered MD (SMD) simulations ( Figure 4 ).…”

Section: Resultsmentioning

confidence: 99%

High-affinity agonist binding to C5aR results from a cooperative two-site binding mechanism

Dumitru

Deepak

Liu

et al. 2020

Preprint

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24A current challenge in the field of life sciences is to decipher, in their native environment, the 25 functional activation of cell surface receptors upon binding of complex ligands. Lack of suitable 26 nanoscopic methods has hampered our ability to meet this challenge in an experimental 27 manner. Here, we use for the first time the interplay between atomic force microscopy, steered 28 molecular dynamics and functional assays to elucidate the complex ligand-binding mechanism 29 of C5a with the human G protein-coupled C5a receptor (C5aR). We have identified two 30 independent binding sites acting in concert where the N-terminal C5aR serves as kinetic trap 31 and the transmembrane domain as functional site. Our results corroborate the two-site binding 32 model and clearly identify a cooperative effect between two binding sites within the C5aR. We 33 anticipate that our methodology could be used for development and design of new therapeutic 34 agents to negatively modulate C5aR activity. 35Introduction 36 The complement C5a anaphylatoxin elicits a variety of immunological responses in vivo (Guo 37 and Ward, 2005), such as the stimulated production of pro-inflammatory cytokine by binding 38 to its cognate cell surface receptor, the G-protein-coupled receptor C5a anaphylatoxin 39 chemotactic receptor 1 (C5aR). This interaction has been a topic of interest in the last couple 40 of decades due to its relevance in several inflammatory pathologies, such as asthma, arthritis, 41 sepsis and more recently Alzheimer's disease and cancer (Ward, 2004; Woodruff, Nandakumar 42 et al., 2011; Klos, Wende et al., 2013). However, the binding mechanism of the C5a ligand to 43 C5aR remains poorly understood at the molecular level hampering the development of new 44 therapeutic agents (Monk, Scola et al., 2007; Klos, Wende et al., 2013). A two-site binding 45 mechanism has been suggested, with the C5a rigid core interacting with both the N-terminus 46 and the second extracellular loop of the receptor (called binding site (BS)) (Siciliano, Rollins et 47 al., 1994), and the C5a flexible C-terminal fragment interacting with the cavity formed by the 48 seven transmembrane (7-TM) helices and involved in the functional activation of C5aR (called 49 effector site (ES)). On one hand, the main interactions at the BS occur between C5aR sulfonated 50 tyrosine residues (Y11 and Y14) and C5a residues R40, R37 and possibly H15 (Siciliano, Rollins 51 et al., 1994; Farzan, Schnitzler et al., 2001; Huber-Lang, Sarma et al., 2003). On the other hand, 52 the C5a R74 is pointed out as a critical residue in the binding to the ES (Siciliano, Rollins et al., 53 1994; Huber-Lang, Sarma et al., 2003). However, given the absence of the structure of the C5a-54 C5aR complex, these interactions have never been directly confirmed. In addition, clear and 55 direct evidence of how these two binding sites could act in concert is missing. Understanding 56 this process is likely to illuminate the binding paradigm common to members of the ...

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“…Blind predictions were carried out on C5aR1 (PDB ID 6C1R [37]), Y1R (PDB ID 5ZBQ [38]), PTAFR (PDB ID 5ZKQ [39]), and D2R (PDB ID 6CM4 [40]). 100 models were generated for each target with RosettaGPCR (black) and the best scoring model was used for analysis.…”

Section: Figure 6: Results Of Novel Structure Prediction From Variousmentioning

confidence: 99%

“…We identified four human GPCR structures that were released following the conclusion of method development. The four structures were C5aR1, Y1R, PTAFR, and D2R (PDB IDs 6C1R [37], 5ZBQ [38], 5ZKQ [39], and 6CM4 [40], respectively). Of note, GPCR-ModSim, which is the only on-demand server we tested, had been updated to include the structures of PTAFR and D2R.…”

Section: Rosettagpcr Outperforms Other Gpcr Modeling Serversmentioning

confidence: 99%

RosettaGPCR: Multiple Template Homology Modeling of GPCRs with Rosetta

Bender

Marlow

Meiler

2019

Preprint

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G-protein coupled receptors (GPCRs) represent a significant target class for pharmaceutical therapies. However, to date, only about 10% of druggable GPCRs have had their structures characterized at atomic resolution. Further, because of the flexibility of GPCRs, alternative conformations remain to be modeled, even after an experimental structure is available. Thus, computational modeling of GPCRs is a crucial component for understanding biological function and to aid development of new therapeutics. Previous single-and multi-template homology modeling protocols in Rosetta often generated non-native-like conformations of transmembrane α-helices and/or extracellular loops. Here we present a new Rosetta protocol for modeling GPCRs that is improved in two critical ways: Firstly, it uses a blended sequence-and structurebased alignment that now accounts for structure conservation in extracellular loops. Secondly, by merging multiple template structures into one comparative model, the best possible template for every region of a target GPCR can be used expanding the conformational space sampled in a meaningful way. This new method allows for accurate modeling of receptors using templates as low as 20% sequence identity, which accounts for nearly the entire druggable space of GPCRs.A model database of all non-odorant GPCRs is made available at www.rosettagpcr.org. Author SummaryStructure-based drug discovery is among the new technologies driving the development of next generation therapeutics. Inherent to this process is the availability of a protein structure for virtual screening. The most heavily drugged protein family, G-protein coupled receptors (GPCRs), however suffers from a lack of experimental structures that could hinder drug development. Technical challenges prevent the determination of every protein structure, so we turn to computational modeling to predict the structures of the remaining proteins. Again, traditional techniques fail due to the high divergence of this family. Here, we build on available methods specifically for the challenge of modeling GPCRs. This new method outperforms other methods and allows for the ability to accurately model nearly 90% of the entire GPCR family.We therefore generate a model database of all GPCRs (www.rosettagpcr.org) for use in future drug development.

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Orthosteric and allosteric action of the C5a receptor antagonists

Cited by 115 publications

References 69 publications

Partial ligand-receptor engagement yields functional bias at the human complement receptor, C5aR1

Partial ligand-receptor engagement yields functional bias at the human complement receptor, C5aR1

High-affinity agonist binding to C5aR results from a cooperative two-site binding mechanism

RosettaGPCR: Multiple Template Homology Modeling of GPCRs with Rosetta

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