8hcr
Cryo-EM structure of the Mycobacterium tuberculosis cytochrome bcc:aa3 supercomplex and a novel inhibitor targeting subunit cytochrome cI
Structural highlights
FunctionQCRB_MYCTU Cytochrome b subunit of the cytochrome bc1 complex, an essential component of the respiratory electron transport chain required for ATP synthesis. The bc1 complex catalyzes the oxidation of ubiquinol and the reduction of cytochrome c in the respiratory chain. The bc1 complex operates through a Q-cycle mechanism that couples electron transfer to generation of the proton gradient that drives ATP synthesis. The cytochrome b subunit contains two ubiquinol reactive sites: the oxidation (QP) site and the reduction (QN) site.[1] [2] Publication Abstract from PubMedThe mycobacterial cytochrome bcc:aa(3) complex deserves the name "supercomplex" since it combines three cytochrome oxidases-cytochrome bc, cytochrome c, and cytochrome aa(3)-into one supramolecular machine and performs electron transfer for the reduction of oxygen to water and proton transport to generate the proton motive force for ATP synthesis. Thus, the bcc:aa(3) complex represents a valid drug target for Mycobacterium tuberculosis infections. The production and purification of an entire M. tuberculosis cytochrome bcc:aa(3) are fundamental for biochemical and structural characterization of this supercomplex, paving the way for new inhibitor targets and molecules. Here, we produced and purified the entire and active M. tuberculosis cyt-bcc:aa(3) oxidase, as demonstrated by the different heme spectra and an oxygen consumption assay. The resolved M. tuberculosis cyt-bcc:aa(3) cryo-electron microscopy structure reveals a dimer with its functional domains involved in electron, proton, oxygen transfer, and oxygen reduction. The structure shows the two cytochrome cIcII head domains of the dimer, the counterpart of the soluble mitochondrial cytochrome c, in a so-called "closed state," in which electrons are translocated from the bcc to the aa(3) domain. The structural and mechanistic insights provided the basis for a virtual screening campaign that identified a potent M. tuberculosis cyt-bcc:aa(3) inhibitor, cytMycc1. cytMycc1 targets the mycobacterium-specific alpha3-helix of cytochrome cI and interferes with oxygen consumption by interrupting electron translocation via the cIcII head. The successful identification of a new cyt-bcc:aa(3) inhibitor demonstrates the potential of a structure-mechanism-based approach for novel compound development. Cryo-Electron Microscopy Structure of the Mycobacterium tuberculosis Cytochrome bcc:aa(3) Supercomplex and a Novel Inhibitor Targeting Subunit Cytochrome cI.,Mathiyazakan V, Wong CF, Harikishore A, Pethe K, Gruber G Antimicrob Agents Chemother. 2023 Jun 15;67(6):e0153122. doi: , 10.1128/aac.01531-22. Epub 2023 May 9. PMID:37158740[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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