8ia2 | pdb_00008ia2

Structure of C5a bound human C5aR1 in complex with Go (Composite map)

Structural highlights

8ia2 is a 6 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.21Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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 complement system is a critical part of our innate immune response, and the terminal products of this cascade, anaphylatoxins C3a and C5a, exert their physiological and pathophysiological responses primarily via two GPCRs, C3aR and C5aR1. However, the molecular mechanism of ligand recognition, activation, and signaling bias of these receptors remains mostly elusive. Here, we present nine cryo-EM structures of C3aR and C5aR1 activated by their natural and synthetic agonists, which reveal distinct binding pocket topologies of complement anaphylatoxins and provide key insights into receptor activation and transducer coupling. We also uncover the structural basis of a naturally occurring mechanism to dampen the inflammatory response of C5a via proteolytic cleavage of the terminal arginine and the G-protein signaling bias elicited by a peptide agonist of C3aR identified here. In summary, our study elucidates the innerworkings of the complement anaphylatoxin receptors and should facilitate structure-guided drug discovery to target these receptors in a spectrum of disorders.

Molecular basis of anaphylatoxin binding, activation, and signaling bias at complement receptors.,Yadav MK, Maharana J, Yadav R, Saha S, Sarma P, Soni C, Singh V, Saha S, Ganguly M, Li XX, Mohapatra S, Mishra S, Khant HA, Chami M, Woodruff TM, Banerjee R, Shukla AK, Gati C Cell. 2023 Oct 26;186(22):4956-4973.e21. doi: 10.1016/j.cell.2023.09.020. Epub , 2023 Oct 17. PMID:37852260^[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:https://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
↑ Yadav MK, Maharana J, Yadav R, Saha S, Sarma P, Soni C, Singh V, Saha S, Ganguly M, Li XX, Mohapatra S, Mishra S, Khant HA, Chami M, Woodruff TM, Banerjee R, Shukla AK, Gati C. Molecular basis of anaphylatoxin binding, activation, and signaling bias at complement receptors. Cell. 2023 Oct 26;186(22):4956-4973.e21. PMID:37852260 doi:10.1016/j.cell.2023.09.020

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OCA

[1] 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

[2] 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

[3] Gerard NP, Gerard C. The chemotactic receptor for human C5a anaphylatoxin. Nature. 1991 Feb 14;349(6310):614-7. PMID:1847994 doi:https://dx.doi.org/10.1038/349614a0

[4] 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

[5] 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

[6] 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

[7] Yadav MK, Maharana J, Yadav R, Saha S, Sarma P, Soni C, Singh V, Saha S, Ganguly M, Li XX, Mohapatra S, Mishra S, Khant HA, Chami M, Woodruff TM, Banerjee R, Shukla AK, Gati C. Molecular basis of anaphylatoxin binding, activation, and signaling bias at complement receptors. Cell. 2023 Oct 26;186(22):4956-4973.e21. PMID:37852260 doi:10.1016/j.cell.2023.09.020

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8ia2 | pdb_00008ia2

Structure of C5a bound human C5aR1 in complex with Go (Composite map)

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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