| Structural highlights
6c1r is a 2 chain structure with sequence from Escherichia coli, Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 2.2Å |
| Ligands: | , , , , , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
C562_ECOLX Electron-transport protein of unknown function.C5AR1_HUMAN Receptor for the chemotactic and inflammatory peptide anaphylatoxin C5a (PubMed:1847994, PubMed:8182049, PubMed:7622471, PubMed:9553099, PubMed:10636859, PubMed:15153520). The ligand interacts with at least two sites on the receptor: a high-affinity site on the extracellular N-terminus, and a second site in the transmembrane region which activates downstream signaling events (PubMed:8182049, PubMed:7622471, PubMed:9553099). Receptor activation stimulates chemotaxis, granule enzyme release, intracellular calcium release and superoxide anion production (PubMed:10636859, PubMed:15153520).[1] [2] [3] [4] [5] [6]
Publication Abstract from PubMed
The C5a receptor (C5aR) is a G-protein-coupled receptor (GPCR) that can induce strong inflammatory response to the anaphylatoxin C5a. Targeting C5aR has emerged as a novel anti-inflammatory therapeutic method. However, developing potent C5aR antagonists as drugs has proven difficult. Here, we report two crystal structures of human C5aR in ternary complexes with the peptide antagonist PMX53 and a non-peptide antagonist, either avacopan or NDT9513727. The structures, together with other biophysical, computational docking and cell-based signaling data, reveal the orthosteric action of PMX53 and its effect of stabilizing the C5aR structure, as well as the allosteric action of chemically diverse non-peptide C5aR antagonists with different binding poses. Structural comparison analysis suggests the presence of similar allosteric sites in other GPCRs. We also discuss critical structural features of C5aR in activation, including a novel conformation of helix 8. On the basis of our results, we suggest novel strategies for developing C5aR-targeting drugs.
Orthosteric and allosteric action of the C5a receptor antagonists.,Liu H, Kim HR, Deepak RNVK, Wang L, Chung KY, Fan H, Wei Z, Zhang C Nat Struct Mol Biol. 2018 Jun;25(6):472-481. doi: 10.1038/s41594-018-0067-z. Epub, 2018 Jun 4. PMID:29867214[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Christophe T, Rabiet MJ, Tardif M, Milcent MD, Boulay F. Human complement 5a (C5a) anaphylatoxin receptor (CD88) phosphorylation sites and their specific role in receptor phosphorylation and attenuation of G protein-mediated responses. Desensitization of C5a receptor controls superoxide production but not receptor sequestration in HL-60 cells. J Biol Chem. 2000 Jan 21;275(3):1656-64. PMID:10636859
- ↑ Postma B, Poppelier MJ, van Galen JC, Prossnitz ER, van Strijp JA, de Haas CJ, van Kessel KP. Chemotaxis inhibitory protein of Staphylococcus aureus binds specifically to the C5a and formylated peptide receptor. J Immunol. 2004 Jun 1;172(11):6994-7001. PMID:15153520
- ↑ Gerard NP, Gerard C. The chemotactic receptor for human C5a anaphylatoxin. Nature. 1991 Feb 14;349(6310):614-7. PMID:1847994 doi:http://dx.doi.org/10.1038/349614a0
- ↑ Monk PN, Barker MD, Partridge LJ, Pease JE. Mutation of glutamate 199 of the human C5a receptor defines a binding site for ligand distinct from the receptor N terminus. J Biol Chem. 1995 Jul 14;270(28):16625-9. PMID:7622471
- ↑ DeMartino JA, Van Riper G, Siciliano SJ, Molineaux CJ, Konteatis ZD, Rosen H, Springer MS. The amino terminus of the human C5a receptor is required for high affinity C5a binding and for receptor activation by C5a but not C5a analogs. J Biol Chem. 1994 May 20;269(20):14446-50. PMID:8182049
- ↑ Chen Z, Zhang X, Gonnella NC, Pellas TC, Boyar WC, Ni F. Residues 21-30 within the extracellular N-terminal region of the C5a receptor represent a binding domain for the C5a anaphylatoxin. J Biol Chem. 1998 Apr 24;273(17):10411-9. PMID:9553099
- ↑ Liu H, Kim HR, Deepak RNVK, Wang L, Chung KY, Fan H, Wei Z, Zhang C. Orthosteric and allosteric action of the C5a receptor antagonists. Nat Struct Mol Biol. 2018 Jun;25(6):472-481. doi: 10.1038/s41594-018-0067-z. Epub, 2018 Jun 4. PMID:29867214 doi:http://dx.doi.org/10.1038/s41594-018-0067-z
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