8ZSK

Complex I from respirasome closed state 1 bound by metformin and CoQ10, alternative orientation (SC-MetC1-ii)

これはPDB形式変換不可エントリーです。

8ZSK の概要

• エントリーDOI: 10.2210/pdb8zsk/pdb
• EMDBエントリー: 60418
• 分子名称: NADH-ubiquinone oxidoreductase chain 4L, Acyl carrier protein, NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 10, mitochondrial, ... (60 entities in total)
• 機能のキーワード: metformin, electron transport chain, respirasome, mammalia, membrane protein
• 由来する生物種: Sus scrofa (pig); 詳細
• タンパク質・核酸の鎖数: 45
• 化学式量合計: 997789.01

構造登録者

Teng, F.,He, Z.X.,Hu, Y.Q.,Xu, C.Y.,Guo, R.Y.,Zhou, L. (登録日: 2024-06-05, 公開日: 2025-11-19, 最終更新日: 2026-02-04)

主引用文献

He, Z.,Teng, F.,Yang, Y.,Guo, R.,Wu, M.,Han, F.,Tian, H.,Wang, J.,Hu, Y.,Jiang, Y.,Zhang, L.,Xu, C.,Yang, F.,Zhou, J.,Zhang, S.,Letts, J.A.,Zhou, R.,Zhou, L.
Hydrophilic metformin and hydrophobic biguanides inhibit mitochondrial complex I by distinct mechanisms.
Nat.Struct.Mol.Biol., 33:100-111, 2026

PubMed Abstract: Metformin is the only antihyperglycemic biguanide targeting type 2 diabetes mellitus with proven safety. Although a mechanism of action involving tight inhibition of the respiratory complex I has been proposed for hydrophobic biguanides, it remains elusive for the hydrophilic metformin, whose excellent pharmacological tolerance depends on weak complex I inhibition without competitive nature. Here we solved cryo-electron microscopy structures of the metformin-bound porcine respirasome. Our structural and kinetic data are consistent with a model in which metformin enters complex I only in its open state and becomes trapped at the ubiquinone redox site by ubiquinone-induced conformational closing of the enzyme. By contrast, the hydrophobic proguanil alone occupies both the entrance and the redox site of the ubiquinone channel in open and closed complex I and is kinetically consistent with competitive inhibition with conformation-dependent affinities. Our data provide the molecular basis for metformin's well-known superior properties, such as a wide therapeutic window and positive ubiquinone cooperativity, leading to its clinical success and facilitating future therapeutic developments.

PubMed: 41214295
DOI: 10.1038/s41594-025-01710-6

実験手法

ELECTRON MICROSCOPY (3.09 Å)