5Z2C

Crystal structure of ALPK-1 N-terminal domain in complex with ADP-heptose

5Z2C の概要

• エントリーDOI: 10.2210/pdb5z2c/pdb
• 分子名称: Alpha-protein kinase 1, [[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanyl-phosphoryl] [(2S,3S,4S,5S,6R)-6-[(1S)-1,2-bis(oxidanyl)ethyl]-3,4,5-tris(oxidanyl)oxan-2-yl] hydrogen phosphate (2 entities in total)
• 機能のキーワード: pattern recognition receptor, kinase, immune system
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 9
• 化学式量合計: 451487.61

構造登録者

Ding, J.,She, Y.,Shao, F. (登録日: 2018-01-02, 公開日: 2018-08-22, 最終更新日: 2024-03-27)

主引用文献

Zhou, P.,She, Y.,Dong, N.,Li, P.,He, H.,Borio, A.,Wu, Q.,Lu, S.,Ding, X.,Cao, Y.,Xu, Y.,Gao, W.,Dong, M.,Ding, J.,Wang, D.C.,Zamyatina, A.,Shao, F.
Alpha-kinase 1 is a cytosolic innate immune receptor for bacterial ADP-heptose.
Nature, 561:122-126, 2018

PubMed Abstract: Immune recognition of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors often activates proinflammatory NF-κB signalling. Recent studies indicate that the bacterial metabolite D-glycero-β-D-manno-heptose 1,7-bisphosphate (HBP) can activate NF-κB signalling in host cytosol, but it is unclear whether HBP is a genuine PAMP and the cognate pattern recognition receptor has not been identified. Here we combined a transposon screen in Yersinia pseudotuberculosis with biochemical analyses and identified ADP-β-D-manno-heptose (ADP-Hep), which mediates type III secretion system-dependent NF-κB activation and cytokine expression. ADP-Hep, but not other heptose metabolites, could enter host cytosol to activate NF-κB. A CRISPR-Cas9 screen showed that activation of NF-κB by ADP-Hep involves an ALPK1 (alpha-kinase 1)-TIFA (TRAF-interacting protein with forkhead-associated domain) axis. ADP-Hep directly binds the N-terminal domain of ALPK1, stimulating its kinase domain to phosphorylate and activate TIFA. The crystal structure of the N-terminal domain of ALPK1 and ADP-Hep in complex revealed the atomic mechanism of this ligand-receptor recognition process. HBP was transformed by host adenylyltransferases into ADP-heptose 7-P, which could activate ALPK1 to a lesser extent than ADP-Hep. ADP-Hep (but not HBP) alone or during bacterial infection induced Alpk1-dependent inflammation in mice. Our findings identify ALPK1 and ADP-Hep as a pattern recognition receptor and an effective immunomodulator, respectively.

PubMed: 30111836
DOI: 10.1038/s41586-018-0433-3

実験手法

X-RAY DIFFRACTION (2.594 Å)