Amporndanai, K, Johnson, RM, O’Neil, PM et al. (6 more authors) (2018) X-ray and cryo-EM structures of inhibitor-bound cytochrome bc₁ complexes for structure-based drug discovery. IUCrJ, 5 (2). pp. 200-210. ISSN 2052-2525
Abstract
Cytochrome bc₁, a dimeric multi-subunit electron-transport protein embedded in the inner mitochondrial membrane, is a major drug target for the treatment and prevention of malaria and toxoplasmosis. Structural studies of cytochrome bc₁ from mammalian homologues co-crystallized with lead compounds have underpinned structure-based drug design to develop compounds with higher potency and selectivity. However, owing to the limited amount of cytochrome bc₁ that may be available from parasites, all efforts have been focused on homologous cytochrome bc₁ complexes from mammalian species, which has resulted in the failure of some drug candidates owing to toxicity in the host. Crystallographic studies of the native parasite proteins are not feasible owing to limited availability of the proteins. Here, it is demonstrated that cytochrome bc₁ is highly amenable to single-particle cryo-EM (which uses significantly less protein) by solving the apo and two inhibitor-bound structures to ∼4.1 Å resolution, revealing clear inhibitor density at the binding site. Therefore, cryo-EM is proposed as a viable alternative method for structure-based drug discovery using both host and parasite enzymes.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) Licence (https://creativecommons.org/licenses/by/2.0/uk/legalcode), which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited. |
Keywords: | cryo-electron microscopy; membrane proteins; electron transport chain, malaria; cryo-EM; cytochrome bc1 |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Biomedical Sciences (Leeds) The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > Cryo EM, Image Processing (Leeds) The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Chemistry (Leeds) |
Funding Information: | Funder Grant number Wellcome Trust 109158/B/15/A |
Depositing User: | Symplectic Publications |
Date Deposited: | 06 Feb 2018 16:59 |
Last Modified: | 25 Jun 2023 21:13 |
Status: | Published |
Publisher: | International Union of Crystallography |
Identification Number: | 10.1107/S2052252518001616 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:127000 |