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Publication Abstract from PubMed

The astacin protease Meprin beta represents an emerging target for drug development due to its potential involvement in disorders such as acute and chronic kidney injury and fibrosis. Here, we elaborate on the structural basis of inhibition by a specific Meprin beta inhibitor. Our analysis of the crystal structure suggests different binding modes of the inhibitor to the active site. This flexibility is caused, at least in part, by movement of the C-terminal region of the protease domain (CTD). The CTD movement narrows the active site cleft upon inhibitor binding. Compared with other astacin proteases, among these the highly homologous isoenzyme Meprin alpha, differences in the subsites account for the unique selectivity of the inhibitor. Although the inhibitor shows substantial flexibility in orientation within the active site, the structural data as well as binding analyses, including molecular dynamics simulations, support a contribution of electrostatic interactions, presumably by arginine residues, to binding and specificity. Collectively, the results presented here and previously support an induced fit and substantial movement of the CTD upon ligand binding and, possibly, during catalysis. To the best of our knowledge, we here present the first structure of a Meprin beta holoenzyme containing a zinc ion and a specific inhibitor bound to the active site. The structural data will guide rational drug design and the discovery of highly potent Meprin inhibitors.

Structure and Dynamics of Meprin beta in Complex with a Hydroxamate-Based Inhibitor.,Linnert M, Fritz C, Jager C, Schlenzig D, Ramsbeck D, Kleinschmidt M, Wermann M, Demuth HU, Parthier C, Schilling S Int J Mol Sci. 2021 May 26;22(11). pii: ijms22115651. doi: 10.3390/ijms22115651. PMID:34073350^[2]

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