8IME
Human cGAS catalytic domain bound with baicalin
Summary for 8IME
| Entry DOI | 10.2210/pdb8ime/pdb |
| Descriptor | 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) |
| Functional Keywords | cgas, inhibitor, baicalin, immune system |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 86542.08 |
| Authors | |
| Primary citation | 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 Cited by 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: 37666112DOI: 10.1016/j.bioorg.2023.106802 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.63 Å) |
Structure validation
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