7R47

Bovine complex I in the presence of IM1761092, deactive class iii (Composite map)

7R47 の概要

• エントリーDOI: 10.2210/pdb7r47/pdb
• EMDBエントリー: 14282 14283 14284 14285 14286
• 分子名称: NADH-ubiquinone oxidoreductase chain 3, NADH-ubiquinone oxidoreductase chain 6, NADH-ubiquinone oxidoreductase chain 4L, ... (60 entities in total)
• 機能のキーワード: complex i, oxidoreductase
• 由来する生物種: Bos taurus (cattle); 詳細
• タンパク質・核酸の鎖数: 45
• 化学式量合計: 1076182.52

構造登録者

Bridges, H.R.,Blaza, J.N.,Yin, Z.,Chung, I.,Hirst, J. (登録日: 2022-02-08, 公開日: 2023-02-08)

主引用文献

Bridges, H.R.,Blaza, J.N.,Yin, Z.,Chung, I.,Pollak, M.N.,Hirst, J.
Structural basis of mammalian respiratory complex I inhibition by medicinal biguanides.
Science, 379:351-357, 2023

PubMed Abstract: 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.

PubMed: 36701435
DOI: 10.1126/science.ade3332

実験手法

ELECTRON MICROSCOPY (2.3 Å)