5o9h
From Proteopedia
Crystal structure of thermostabilised human C5a anaphylatoxin chemotactic receptor 1 (C5aR) in complex with NDT9513727
Structural highlights
FunctionC5AR1_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 PubMedThe 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
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Categories: Homo sapiens | Large Structures | Bottegoni G | Brown J | Cansfield J | Cooke RM | Dore AS | Jazayeri A | Koglin M | Marshall FH | Rappas M | Robertson N
