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

IUCrJ
Kangsa AmporndanaiSvetlana V Antonyuk

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.

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Citations

Jun 24, 2020·FEBS Letters·Nicholas FisherGiancarlo A Biagini
Sep 11, 2019·Bioinformatics·Erney Ramírez-AportelaCarlos Oscar S Sorzano
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Feb 23, 2021·Molecular Biology and Evolution·Giovanni PiccininiFabrizio Ghiselli
Feb 25, 2020·ACS Infectious Diseases·Shi Min Sherilyn ChongGerhard Grüber
Nov 12, 2021·Molecular Diversity·Mushtaq Ahmad Wani, Devendra Kumar Dhaked

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Methods Mentioned

BETA
X-ray
ion-exchange
gel filtration

Software Mentioned

MDFF
RELION
MOLREP
MotionCor
PHENIX
EPU
REFMAC
UCSF Chimera
Coot
AIMLESS

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