A structural mechanism of flavonoids in inhibiting serine proteases

作者：Xue, Guangpu; Gong, Lihu; Yuan, Cai; Xu, Mingming; Wang, Xu; Jiang, Longguang^*; Huang, Mingdong^*

来源：Food & Function, 2017, 8(7): 2437-2443.

DOI：10.1039/c6fo01825d

• NATURAL OCCURRING POLYPHENOLS
• PLASMINOGEN-ACTIVATOR
• THROMBIN INHIBITORS
• PLANT FLAVONOIDS
• TRYPSIN-LIKE
• IN-VITRO
• UROKINASE
• SPECIFICITY
• DOMAIN
• CRYSTALLOGRAPHY

Quercetin is a member of the flavonoids and was previously demonstrated to inhibit trypsin-like serine proteases at micromolar potencies. Different molecular models were proposed to explain such inhibition. However, controversies remain on the molecular details of inhibition. Here, we report the X-ray crystal structure of quercetin in a complex with the urokinase-type plasminogen activator (uPA), an archetypical serine protease. The structure showed that quercetin binds to the specific substrate binding pocket (S1 pocket) of uPA mainly through its two neighboring phenolic hydroxyl groups. Our study thus provides unambiguous evidence to support quercetin binding to serine proteases and defines the molecular basis of the interaction. Our results further establish that natural products with two adjacent phenolic hydroxyl groups (or catechol) are likely to inhibit other trypsin-like serine proteases, a new mechanism formerly under-recognized.

• 出版日期2017-7-1
• 单位福建师范大学; 中国科学院福建物质结构研究所; 福州大学; 结构化学国家重点实验室