A structural mechanism of flavonoids in inhibiting serine proteases
A structural mechanism of flavonoids in inhibiting serine proteases
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黄酮类化合物抑制丝氨酸蛋白酶的结构机制
DOI：
10.1039/c6fo01825d
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发表时间：
2017
期刊：
影响因子：
6.1
通讯作者：
Huang Mingdong
中科院分区：
文献类型：
--
作者：
Xue Guangpu;Gong Lihu;Yuan Cai;Xu Mingming;Wang Xu;Jiang Longguang;Huang Mingdong
槲皮素是黄酮类化合物的一种，之前已被证明能够以微摩尔浓度抑制胰蛋白酶样丝氨酸蛋白酶。提出了不同的分子模型来解释这种抑制。然而，抑制的分子细节仍然存在争议。在这里，我们报告了槲皮素与尿激酶型纤溶酶原激活剂（uPA）（一种典型的丝氨酸蛋白酶）复合物的 X 射线晶体结构。结构表明槲皮素主要通过其两个相邻的酚羟基与uPA的特异性底物结合袋（S1袋）结合。因此，我们的研究提供了明确的证据来支持槲皮素与丝氨酸蛋白酶的结合，并确定了相互作用的分子基础。我们的结果进一步证实，具有两个相邻酚羟基（或儿茶酚）的天然产物可能会抑制其他胰蛋白酶样丝氨酸蛋白酶，这是一种以前未被充分认识的新机制。
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.