9FU0

CIII2/CIV respiratory chain supercomplex from Mycobacterium smegmatis

Summary for 9FU0

• Entry DOI: 10.2210/pdb9fu0/pdb
• Related: 9FTZ
• EMDB information: 50753
• Descriptor: Cytochrome bc1 complex cytochrome c subunit, Uncharacterized protein MSMEG_4692/MSMEI_4575, LpqE protein, ... (30 entities in total)
• Functional Keywords: respiratory supercomplex, membrane protein, actinobacteria, electron transport
• Biological source: Mycolicibacterium smegmatis; More
• Total number of polymer chains: 15
• Total formula weight: 521814.84

Authors

Kovalova, T.,Krol, S.,Gamiz-Hernandez, A.,Sjostrand, D.,Kaila, V.,Brzezinski, P.,Hogbom, M. (deposition date: 2024-06-25, release date: 2024-11-20, Last modification date: 2024-11-27)

Primary citation

Kovalova, T.,Krol, S.,Gamiz-Hernandez, A.P.,Sjostrand, D.,Kaila, V.R.I.,Brzezinski, P.,Hogbom, M.
Inhibition mechanism of potential antituberculosis compound lansoprazole sulfide.
Proc.Natl.Acad.Sci.USA, 121:e2412780121-e2412780121, 2024

PubMed Abstract: Tuberculosis is one of the most common causes of death worldwide, with a rapid emergence of multi-drug-resistant strains underscoring the need for new antituberculosis drugs. Recent studies indicate that lansoprazole-a known gastric proton pump inhibitor and its intracellular metabolite, lansoprazole sulfide (LPZS)-are potential antituberculosis compounds. Yet, their inhibitory mechanism and site of action still remain unknown. Here, we combine biochemical, computational, and structural approaches to probe the interaction of LPZS with the respiratory chain supercomplex IIIIV of , a close homolog of supercomplex. We show that LPZS binds to the Q cavity of the mycobacterial supercomplex, inhibiting the quinol substrate oxidation process and the activity of the enzyme. We solve high-resolution (2.6 Å) cryo-electron microscopy (cryo-EM) structures of the supercomplex with bound LPZS that together with microsecond molecular dynamics simulations, directed mutagenesis, and functional assays reveal key interactions that stabilize the inhibitor, but also how mutations can lead to the emergence of drug resistance. Our combined findings reveal an inhibitory mechanism of LPZS and provide a structural basis for drug development against tuberculosis.

PubMed: 39531492
DOI: 10.1073/pnas.2412780121

Experimental method

ELECTRON MICROSCOPY (2.7 Å)