Bridges, Hannah R, Blaza, James N orcid.org/0000-0001-5420-2116, Yin, Zhan et al. (3 more authors) (2023) Structural basis of mammalian respiratory complex I inhibition by medicinal biguanides. Science (New York, N.Y.). pp. 351-357. ISSN 0036-8075
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details |
Keywords: | Animals,Electron Transport Complex I/metabolism,Cryoelectron Microscopy,Metformin/pharmacology,Antimalarials/pharmacology,Mitochondria/metabolism,Mammals |
Dates: |
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Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Chemistry (York) |
Depositing User: | Pure (York) |
Date Deposited: | 22 Mar 2023 09:30 |
Last Modified: | 07 Feb 2025 00:35 |
Published Version: | https://doi.org/10.1126/science.ade3332 |
Status: | Published |
Refereed: | Yes |
Identification Number: | 10.1126/science.ade3332 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:197522 |