Structural highlights
FunctionUCRI_BOVIN Component of the ubiquinol-cytochrome c reductase complex (complex III or cytochrome b-c1 complex), which is a respiratory chain that generates an electrochemical potential coupled to ATP synthesis. The transit peptide of the Rieske protein seems to form part of the bc1 complex and is considered to be the subunit 11/IX of that complex. Publication Abstract from PubMedCytochrome 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 approximately 4.1 A 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. X-ray and cryo-EM structures of inhibitor-bound cytochrome bc1 complexes for structure-based drug discovery.,Amporndanai K, Johnson RM, O'Neill PM, Fishwick CWG, Jamson AH, Rawson S, Muench SP, Hasnain SS, Antonyuk SV IUCrJ. 2018 Feb 20;5(Pt 2):200-210. doi: 10.1107/S2052252518001616. eCollection, 2018 Mar 1. PMID:29765610[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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