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Publication Abstract from PubMed

Zinc metalloprotease 1 (Zmp1), a Mycobacterium tuberculosis 75 kDa secreted enzyme, mediates key stages of tuberculosis disease progression. The biological activity of Zmp1 presumably stems from its ability to degrade bacterium- and/or host-derived peptides. The crystal structures of Zmp1 and related M13 metalloproteases, such as neprilysin and endothelin-converting enzyme-1 were determined only in the closed conformation, which cannot capture substrates or release proteolytic products. Thus, the mechanisms of substrate binding and selectivity remain elusive. Here we report two open-state cryo-EM structures of Zmp1, revealed by our SAXS analysis to be the dominant states in solution. Our structural analyses reveal how ligand binding induces a conformational switch in four linker regions to drive the rigid body motion of the D1 and D2 domains, which form the sizable catalytic chamber. Furthermore, they offer insights into the catalytic cycle and mechanism of substrate recognition of M13 metalloproteases for future therapeutic innovations.

Structural analysis of Mycobacteriumtuberculosis M13 metalloprotease Zmp1 open states.,Liang WG, Mancl JM, Zhao M, Tang WJ Structure. 2020 Dec 22. pii: S0969-2126(20)30469-X. doi:, 10.1016/j.str.2020.12.002. PMID:33378640^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.