8IME

Human cGAS catalytic domain bound with baicalin

8IME の概要

• エントリーDOI: 10.2210/pdb8ime/pdb
• 分子名称: Cyclic GMP-AMP synthase, 5,6-dihydroxy-4-oxo-2-phenyl-4H-chromen-7-yl beta-D-glucopyranosiduronic acid, ZINC ION, ... (4 entities in total)
• 機能のキーワード: cgas, inhibitor, baicalin, immune system
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 86542.08

構造登録者

Zhao, W.F.,Xu, Y.C. (登録日: 2023-03-06, 公開日: 2024-01-03)

主引用文献

Li, J.,Xiong, M.,Liu, J.,Zhang, F.,Li, M.,Zhao, W.,Xu, Y.
Discovery of novel cGAS inhibitors based on natural flavonoids.
Bioorg.Chem., 140:106802-106802, 2023

PubMed Abstract: Cyclic GMP-AMP synthase (cGAS) plays an important role in the inflammatory response. It has been reported that aberrant activation of cGAS is associated with a variety of immune-mediated inflammatory disorders. The development of small molecule inhibitors of cGAS has been considered as a promising therapeutic strategy for the diseases. Flavonoids, a typical class of natural products, are known for their anti-inflammatory activities. Although cGAS is closely associated with inflammation, the potential effects of natural flavonoid compounds on cGAS have been rarely studied. Therefore, we screened an in-house natural flavonoid library by pyrophosphatase (PPase) coupling assay and identified novel cGAS inhibitors baicalein and baicalin. Subsequently, crystal structures of the two natural flavonoids in complex with human cGAS were determined, which provide mechanistic insight into the anti-inflammatory activities of baicalein and baicalin at the molecular level. After that, a virtual screening based on the crystal structures of baicalein and baicalin in complex with human cGAS was performed. As a result, compound C20 was identified to inhibit both human and mouse cGAS with IC values of 2.28 and 1.44 μM, respectively, and its detailed interactions with human cGAS were further revealed by the X-ray crystal structure determination. These results demonstrate the potential of natural products used as hits in drug discovery and provide valuable hints for further development of cGAS inhibitors.

PubMed: 37666112
DOI: 10.1016/j.bioorg.2023.106802

実験手法

X-RAY DIFFRACTION (2.63 Å)