Abstract
Tuberculosis continues to be a major threat to the human population. Global efforts to eradicate the disease are ongoing but are hampered by the increasing occurrence of multidrug-resistant strains of Mycobacterium tuberculosis. Therefore, the development of new treatment, and the exploration of new druggable targets and treatment strategies, are of high importance. Rv0183/mtbMGL, is a monoacylglycerol lipase of M. tuberculosis and it is involved in providing fatty acids and glycerol as building blocks and as an energy source. Since the lipase is expressed during the dormant and active phase of an infection, Rv0183/mtbMGL is an interesting target for inhibition. In this work, we determined the crystal structures of a surface-entropy reduced variant K74A Rv0183/mtbMGL in its free form and in complex with a substrate mimicking inhibitor. The two structures reveal conformational changes in the cap region that forms a major part of the substrate/inhibitor binding region. We present a completely closed conformation in the free form and semi-closed conformation in the ligand-bound form. These conformations differ from the previously published, completely open conformation of Rv0183/mtbMGL. Thus, this work demonstrates the high conformational plasticity of the cap from open to closed conformations and provides useful insights into changes in the substrate-binding pocket, the target of potential small-molecule inhibitors.
Highlights
To improve the success rate of our crystallization trials, we introduced surface-entropy reduction (SER) mutations on the gene of the success rate of our crystallization trials, we introduced SER mutations on the gene of mtbMGL.The
The N-terminal loop of the cap domain, connecting β-strand 6 of the α/β-hydrolase core fold with the first helix in the cap domain, forms a single turn of a 310 helix
Extensive research was performed on the relationship between conformational changes in the cap domain of homolog MGL (hMGL), and their activities in relation to open and closed states [19,22,24,25,42]
Summary
Tuberculosis (TB) is one of the top causes of death from a communicable disease worldwide and a predominant cause of death from a single infectious agent, even during the ongoing COVID-19 pandemic. Despite a steady decline of case numbers over the last few decades, only a few countries are on track to achieve the goals set by the WHO and their “End TB” Strategy. Infections with the etiologic agent Mycobacterium tuberculosis (Mtb) and the occurrence of multidrug- and rifampicin-resistant strains (MDR/RR-TB) [1] will likely be further accelerated, even though the reported case numbers dropped significantly during 2020. The drop is likely attributed to the restriction of movement, personal economic impacts, and global reallocation of resources to the COVID-19 response. The first modeling attempts suggest a rise in the TB death rate in the upcoming years, which further increases the demand for new treatment strategies
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