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Article

Structure and Dynamics of Meprin β in Complex with a Hydroxamate-Based Inhibitor

1
Fraunhofer Institute for Cell Therapy and Immunology, Department of Drug Design and Target Validation, Weinbergweg 22, 06120 Halle (Saale), Germany
2
Vivoryon Therapeutics N. V., Weinbergweg 22, 06120 Halle (Saale), Germany
3
Faculty of Applied Biosciences and Process Engineering, Anhalt University of Applied Sciences, Bernburger Street 55, 06366 Köthen, Germany
4
Institute of Biochemistry and Biotechnology, Charles-Tanford-Proteinzentrum, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Street 3a, 06120 Halle (Saale), Germany
*
Authors to whom correspondence should be addressed.
Both authors contributed equally.
Academic Editor: Tatyana Karabencheva-Christova
Int. J. Mol. Sci. 2021, 22(11), 5651; https://doi.org/10.3390/ijms22115651
Received: 5 May 2021 / Revised: 21 May 2021 / Accepted: 21 May 2021 / Published: 26 May 2021
(This article belongs to the Collection Proteins and Protein-Ligand Interactions)
The astacin protease Meprin β 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 β 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 α, 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 β 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. View Full-Text
Keywords: Meprin B; Meprin beta; metalloproteinase; astacin; hydroxamate; SAR (structure activity relationship); MWT-S-270 Meprin B; Meprin beta; metalloproteinase; astacin; hydroxamate; SAR (structure activity relationship); MWT-S-270
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MDPI and ACS Style

Linnert, M.; Fritz, C.; Jäger, C.; Schlenzig, D.; Ramsbeck, D.; Kleinschmidt, M.; Wermann, M.; Demuth, H.-U.; Parthier, C.; Schilling, S. Structure and Dynamics of Meprin β in Complex with a Hydroxamate-Based Inhibitor. Int. J. Mol. Sci. 2021, 22, 5651. https://doi.org/10.3390/ijms22115651

AMA Style

Linnert M, Fritz C, Jäger C, Schlenzig D, Ramsbeck D, Kleinschmidt M, Wermann M, Demuth H-U, Parthier C, Schilling S. Structure and Dynamics of Meprin β in Complex with a Hydroxamate-Based Inhibitor. International Journal of Molecular Sciences. 2021; 22(11):5651. https://doi.org/10.3390/ijms22115651

Chicago/Turabian Style

Linnert, Miriam, Claudia Fritz, Christian Jäger, Dagmar Schlenzig, Daniel Ramsbeck, Martin Kleinschmidt, Michael Wermann, Hans-Ulrich Demuth, Christoph Parthier, and Stephan Schilling. 2021. "Structure and Dynamics of Meprin β in Complex with a Hydroxamate-Based Inhibitor" International Journal of Molecular Sciences 22, no. 11: 5651. https://doi.org/10.3390/ijms22115651

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