Structure and Dynamics of Meprin β in Complex with a Hydroxamate-Based Inhibitor
| Autor: | Daniel Ramsbeck, Christoph Parthier, Hans-Ulrich Demuth, Stephan Schilling, Miriam Linnert, Michael Wermann, Martin Kleinschmidt, Claudia Fritz, Dagmar Schlenzig, Christian Jäger |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Proteases Arginine QH301-705.5 medicine.medical_treatment Drug design Molecular Dynamics Simulation hydroxamate Hydroxamic Acids 01 natural sciences Isozyme Catalysis Article MWT-S-270 Inorganic Chemistry 03 medical and health sciences Structure-Activity Relationship 0103 physical sciences medicine Humans Protease Inhibitors Physical and Theoretical Chemistry Biology (General) Molecular Biology QD1-999 Meprin B Spectroscopy Metalloproteinase Protease 010304 chemical physics biology Chemistry Organic Chemistry SAR (structure activity relationship) Active site Metalloendopeptidases General Medicine Meprin beta Computer Science Applications 030104 developmental biology Biochemistry biology.protein metalloproteinase Astacin astacin |
| Zdroj: | International Journal of Molecular Sciences International Journal of Molecular Sciences, Vol 22, Iss 5651, p 5651 (2021) Volume 22 Issue 11 |
| ISSN: | 1422-0067 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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