6C1R

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

6C1R の概要

• エントリーDOI: 10.2210/pdb6c1r/pdb
• 関連するPDBエントリー: 6C1Q
• 関連するBIRD辞書のPRD_ID: PRD_002303
• 分子名称: Soluble cytochrome b562, C5a anaphylatoxin chemotactic receptor 1 chimera, PMX53, avacopan, ... (9 entities in total)
• 機能のキーワード: gpcr, membrane protein-inhibitor complex, membrane protein/inhibitor
• 由来する生物種: Escherichia coli; 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 51206.42

構造登録者

Liu, H.,Wang, L.,Wei, Z.,Zhang, C. (登録日: 2018-01-05, 公開日: 2018-05-30, 最終更新日: 2023-11-15)

主引用文献

Liu, H.,Kim, H.R.,Deepak, R.N.V.K.,Wang, L.,Chung, K.Y.,Fan, H.,Wei, Z.,Zhang, C.
Orthosteric and allosteric action of the C5a receptor antagonists.
Nat. Struct. Mol. Biol., 25:472-481, 2018

PubMed Abstract: 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.

PubMed: 29867214
DOI: 10.1038/s41594-018-0067-z

実験手法

X-RAY DIFFRACTION (2.2 Å)