6FO0

CryoEM structure of bovine cytochrome bc1 in complex with the anti-malarial compound GSK932121

Summary for 6FO0

• Entry DOI: 10.2210/pdb6fo0/pdb
• EMDB information: 4286 8657
• Descriptor: Cytochrome b-c1 complex subunit 1, mitochondrial, Cytochrome b-c1 complex subunit 9, PROTOPORPHYRIN IX CONTAINING FE, ... (13 entities in total)
• Functional Keywords: cryo-em, inhibitor binding, membrane protein, cytochrome bc1
• Biological source: Bos taurus (Bovine); More
• Total number of polymer chains: 20
• Total formula weight: 507986.26

Authors

Johnson, R.M.,Amporndanai, K.,O'Neill, P.M.,Fishwick, C.W.G.,Jamson, A.H.,Rawson, S.D.,Hasnain, S.S.,Antonyuk, S.V.,Muench, S.P. (deposition date: 2018-02-05, release date: 2018-02-28, Last modification date: 2019-12-11)

Primary citation

Amporndanai, K.,Johnson, R.M.,O'Neill, P.M.,Fishwick, C.W.G.,Jamson, A.H.,Rawson, S.,Muench, S.P.,Hasnain, S.S.,Antonyuk, S.V.
X-ray and cryo-EM structures of inhibitor-bound cytochromebc1complexes for structure-based drug discovery.
IUCrJ, 5:200-210, 2018

PubMed Abstract: Cytochrome , 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 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 that may be available from parasites, all efforts have been focused on homologous cytochrome 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 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.

PubMed: 29765610
DOI: 10.1107/S2052252518001616

Experimental method

ELECTRON MICROSCOPY (4.1 Å)