双胍
化学
药物作用
药品
结合位点
酶
行动方式
生物化学
药理学
生物物理学
立体化学
二甲双胍
生物
糖尿病
内分泌学
作者
Hannah R. Bridges,James N. Blaza,Zhan Yin,Injae Chung,Michael Pollak,Judy Hirst
出处
期刊:Science
[American Association for the Advancement of Science (AAAS)]
日期:2023-01-27
卷期号:379 (6630): 351-357
被引量:32
标识
DOI:10.1126/science.ade3332
摘要
The molecular mode of action of biguanides, including the drug metformin, which is widely used in the treatment of diabetes, is incompletely characterized. Here, we define the inhibitory drug-target interaction(s) of a model biguanide with mammalian respiratory complex I by combining cryo–electron microscopy and enzyme kinetics. We interpret these data to explain the selectivity of biguanide binding to different enzyme states. The primary inhibitory site is in an amphipathic region of the quinone-binding channel, and an additional binding site is in a pocket on the intermembrane-space side of the enzyme. An independent local chaotropic interaction, not previously described for any drug, displaces a portion of a key helix in the membrane domain. Our data provide a structural basis for biguanide action and enable the rational design of medicinal biguanides.
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