7R42

Bovine complex I in the presence of IM1761092, active class ii (Composite map)

Summary for 7R42

• Entry DOI: 10.2210/pdb7r42/pdb
• EMDB information: 14256 14257 14258 14259 14260
• Descriptor: NADH-ubiquinone oxidoreductase chain 3, NADH-ubiquinone oxidoreductase chain 6, NADH-ubiquinone oxidoreductase chain 4L, ... (60 entities in total)
• Functional Keywords: complex i, oxidoreductase
• Biological source: Bos taurus (cattle); More
• Total number of polymer chains: 45
• Total formula weight: 1080219.82

Authors

Bridges, H.R.,Blaza, J.N.,Yin, Z.,Chung, I.,Hirst, J. (deposition date: 2022-02-08, release date: 2023-02-08)

Primary citation

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

Experimental method

ELECTRON MICROSCOPY (2.3 Å)