9J6H
Complex I from respirasome closed state 1 bound by metformin and CoQ10 (SC-MetC1-iv)
This is a non-PDB format compatible entry.
Summary for 9J6H
| Entry DOI | 10.2210/pdb9j6h/pdb |
| EMDB information | 61173 |
| Descriptor | NADH-ubiquinone oxidoreductase chain 4L, Acyl carrier protein, NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 10, mitochondrial, ... (59 entities in total) |
| Functional Keywords | metformin, electron transport chain, respirasome, membrane protein |
| Biological source | Sus scrofa (pig) More |
| Total number of polymer chains | 45 |
| Total formula weight | 989383.24 |
| Authors | |
| Primary citation | 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., 2025 Cited by 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: 41214295DOI: 10.1038/s41594-025-01710-6 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.92 Å) |
Structure validation
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