6c1q

Crystal structure of human C5a receptor in complex with an orthosteric antagonist PMX53 and an allosteric antagonist NDT9513727

spinqualitylabelsall models 6c1q, resolution 2.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6c1q 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 2.9Å Ligands: 9P2, ACE, ORN, YCM, ZAL 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). 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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