Structural basis of mammalian respiratory complex I inhibition by medicinal biguanides

Hannah R Bridges; James N Blaza; Zhan Yin; Injae Chung; Michael N Pollak; Judy Hirst

doi:10.1126/science.ade3332

Structural basis of mammalian respiratory complex I inhibition by medicinal biguanides

Hannah R Bridges, James N Blaza, Zhan Yin, Injae Chung, Michael N Pollak, Judy Hirst

Chemistry

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	351-357
Number of pages	7
Journal	Science (New York, N.Y.)
Volume	379
Issue number	6630
DOIs	https://doi.org/10.1126/science.ade3332
Publication status	Published - 27 Jan 2023

Bibliographical note

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

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10.1126/science.ade3332

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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
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Cite this

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title = "Structural basis of mammalian respiratory complex I inhibition by medicinal biguanides",

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.",

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AU - Bridges, Hannah R

AU - Blaza, James N

AU - Yin, Zhan

AU - Chung, Injae

AU - Pollak, Michael N

AU - Hirst, Judy

N1 - 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

PY - 2023/1/27

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N2 - 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.

AB - 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.

KW - Animals

KW - Electron Transport Complex I/metabolism

KW - Cryoelectron Microscopy

KW - Metformin/pharmacology

KW - Antimalarials/pharmacology

KW - Mitochondria/metabolism

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