Using Cryo-EM Structure of the Mycobacterial Cytochrome bcc-aa3 Supercomplex to Decrypt the Binding Mechanism of its Substrate(s) and Known Inhibitors

The continuously increasing incidence of drug-resistant tuberculosis has become a serious health challenge in developing countries. There is a need for innovative approaches for the identification of new targets and discovery of novel drug candidates against resistant Mycobacterium tuberculosis (Mtb). The oxidative phosphorylation pathway of mycobacteria has emerged as a novel target pathway for the discovery of many drug candidates. The mycobacterial Cytochrome bcc-aa3 supercomplex plays a vital role in the electron transport chain for the survival of mycobacterium. Q203 is a Phase-II clinical candidate targeting the inhibiton of mycobacterial Cytochrome bcc-aa3 supercomplex. Recent availability of Cryo-EM structure of this supercomplex motivated us to explore the molecular mechanism of its inhibition by small molecules like Q203. The cryo-EM structure revealed two substrate (quinone/quinol) binding sites, namely QP and QN. The QP site is nearer to the Heme bL of QcrB subunit responsible for the menaquinol (MKH2) oxidation and the QN site near to Heme bH of QcrB subunit responsible for the menaquinone reduction that may be able to accommodate a variety of small-molecule inhibitors. The InducedFit studies revealed that menaquinol (substrate) and known inhibitors like, Q203 and Lansoprazole metabolite bind deeper into the site proximal to hydrophobic residues of QcrBALa173, QcrBLeu175, QcrBTyr159, QcrBThr308, and QcrBAsp309. Further insights gained in this study will be presented in the poster.