X-ray and cryo-EM structures of inhibitor-bound cytochrome bc1 complexes for structure-based drug discovery



Amporndanai, Kangsa, Johnson, Rachel M, O'Neill, Paul ORCID: 0000-0003-4338-0317, Fishwick, Colin WG, Jamson, Alexander H, Rawson, Shaun, Muench, Stephen P, Antonyuk, SV ORCID: 0000-0002-2779-9946 and Hasnain, Samar
(2018) X-ray and cryo-EM structures of inhibitor-bound cytochrome bc1 complexes for structure-based drug discovery. IUCrJ, 5 (Pt 2). 200 - 210.

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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.

Item Type: Article
Uncontrolled Keywords: cryo-electron microscopy, cryo-EM, membrane proteins, electron-transport chain, malaria, cytochrome bc1
Depositing User: Symplectic Admin
Date Deposited: 21 Feb 2018 12:52
Last Modified: 25 Nov 2021 21:10
DOI: 10.1107/S2052252518001616
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3018298