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Structure and dynamics of Meprin β in complex with a hydroxamate-based inhibitor

DOI: 10.3390/ijms22115651 DOI Help

Authors: Miriam Linnert (Fraunhofer Institute for Cell Therapy and Immunology) , Claudia Fritz (Fraunhofer Institute for Cell Therapy and Immunology) , Christian Jäger (Vivoryon Therapeutics N. V.) , Dagmar Schlenzig (Fraunhofer Institute for Cell Therapy and Immunology) , Daniel Ramsbeck (Fraunhofer Institute for Cell Therapy and Immunology) , Martin Kleinschmidt (Fraunhofer Institute for Cell Therapy and Immunology) , Michael Wermann (Fraunhofer Institute for Cell Therapy and Immunology) , Hans-Ulrich Demuth (Fraunhofer Institute for Cell Therapy and Immunology; Anhalt University of Applied Sciences) , Christoph Parthier (Martin-Luther-University Halle-Wittenberg) , Stephan Schilling (Fraunhofer Institute for Cell Therapy and Immunology; Anhalt University of Applied Sciences)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: International Journal Of Molecular Sciences , VOL 22

State: Published (Approved)
Published: May 2021

Open Access Open Access

Abstract: 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.

Journal Keywords: Meprin B; Meprin beta; metalloproteinase; astacin; hydroxamate; SAR (structure activity relationship); MWT-S-270

Diamond Keywords: Enzymes

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I03-Macromolecular Crystallography

Added On: 02/06/2021 09:19

Documents:
ijms-22-05651.pdf

Discipline Tags:

Life Sciences & Biotech Health & Wellbeing Drug Discovery Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)