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X-ray and cryo-EM structures of inhibitor-bound cytochrome bc 1 complexes for structure-based drug discovery

DOI: 10.1107/S2052252518001616 DOI Help

Authors: Kangsa Amporndanai (University of Liverpool) , Rachel M. Johnson (University of Leeds) , Paul M. O'neill (University of Liverpool) , Colin W. G. Fishwick (University of Leeds) , Alexander H. Jamson (University of Leeds) , Shaun Rawson (University of Leeds) , Stephen Muench (University of Leeds) , S. Samar Hasnain (University of Liverpool) , Svetlana V. Antonyuk (University of Liverpool)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Iucrj , VOL 5

State: Published (Approved)
Published: March 2018
Diamond Proposal Number(s): 11740

Open Access Open Access

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.

Journal Keywords: cryo-electron microscopy; cryo-EM; membrane proteins; electron-transport chain; malaria; cytochrome bc1

Subject Areas: Biology and Bio-materials, Medicine

Instruments: I03-Macromolecular Crystallography