Back to Search Start Over

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

Authors :
Kangsa Amporndanai
Rachel M. Johnson
Paul M. O'Neill
Colin W. G. Fishwick
Alexander H. Jamson
Shaun Rawson
Stephen P. Muench
S. Samar Hasnain
Svetlana V. Antonyuk
Source :
IUCrJ, Vol 5, Iss 2, Pp 200-210 (2018)
Publication Year :
2018
Publisher :
International Union of Crystallography, 2018.

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.

Details

Language :
English
ISSN :
20522525
Volume :
5
Issue :
2
Database :
Directory of Open Access Journals
Journal :
IUCrJ
Publication Type :
Academic Journal
Accession number :
edsdoj.9927769951f4f6387d594d9fbff2534
Document Type :
article
Full Text :
https://doi.org/10.1107/S2052252518001616