5o9h

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Crystal structure of thermostabilised human C5a anaphylatoxin chemotactic receptor 1 (C5aR) in complex with NDT9513727Crystal structure of thermostabilised human C5a anaphylatoxin chemotactic receptor 1 (C5aR) in complex with NDT9513727

Structural highlights

5o9h is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.7Å
Ligands:, , ,
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 crucial component of the host response to infection and tissue damage. Activation of the complement cascade generates anaphylatoxins including C5a and C3a. C5a exerts a pro-inflammatory effect via the G-protein-coupled receptor C5a anaphylatoxin chemotactic receptor 1 (C5aR1, also known as CD88) that is expressed on cells of myeloid origin. Inhibitors of the complement system have long been of interest as potential drugs for the treatment of diseases such as sepsis, rheumatoid arthritis, Crohn's disease and ischaemia-reperfusion injuries. More recently, a role of C5a in neurodegenerative conditions such as Alzheimer's disease has been identified. Peptide antagonists based on the C5a ligand have progressed to phase 2 trials in psoriasis and rheumatoid arthritis; however, these compounds exhibited problems with off-target activity, production costs, potential immunogenicity and poor oral bioavailability. Several small-molecule competitive antagonists for C5aR1, such as W-54011 and NDT9513727, have been identified by C5a radioligand-binding assays. NDT9513727 is a non-peptide inverse agonist of C5aR1, and is highly selective for the primate and gerbil receptors over those of other species. Here, to study the mechanism of action of C5a antagonists, we determine the structure of a thermostabilized C5aR1 (known as C5aR1 StaR) in complex with NDT9513727. We found that the small molecule bound between transmembrane helices 3, 4 and 5, outside the helical bundle. One key interaction between the small molecule and residue Trp213(5.49) seems to determine the species selectivity of the compound. The structure demonstrates that NDT9513727 exerts its inverse-agonist activity through an extra-helical mode of action.

Structure of the complement C5a receptor bound to the extra-helical antagonist NDT9513727.,Robertson N, Rappas M, Dore AS, Brown J, Bottegoni G, Koglin M, Cansfield J, Jazayeri A, Cooke RM, Marshall FH Nature. 2018 Jan 3;553(7686):111-114. doi: 10.1038/nature25025. PMID:29300009[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  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:http://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. ↑ Robertson N, Rappas M, Dore AS, Brown J, Bottegoni G, Koglin M, Cansfield J, Jazayeri A, Cooke RM, Marshall FH. Structure of the complement C5a receptor bound to the extra-helical antagonist NDT9513727. Nature. 2018 Jan 3;553(7686):111-114. doi: 10.1038/nature25025. PMID:29300009 doi:http://dx.doi.org/10.1038/nature25025

5o9h, resolution 2.70Å

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