7AQ1

Crystal structure of human mature meprin beta in complex with the specific inhibitor MWT-S-270

Summary for 7AQ1

• Entry DOI: 10.2210/pdb7aq1/pdb
• Descriptor: Meprin B subunit beta, 2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (11 entities in total)
• Functional Keywords: astacin protease, metalloproteinase, zn dependent, sheddase, gamma secretase, inhbibitor bound meprin beta holoenzyme, intermolecular disulfide bridge homodimer, glycoprotein, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 127877.33

Authors

Linnert, M.,Parthier, C.,Fritz, C. (deposition date: 2020-10-20, release date: 2021-03-03, Last modification date: 2024-11-06)

Primary citation

Linnert, M.,Fritz, C.,Jager, C.,Schlenzig, D.,Ramsbeck, D.,Kleinschmidt, M.,Wermann, M.,Demuth, H.U.,Parthier, C.,Schilling, S.
Structure and Dynamics of Meprin beta in Complex with a Hydroxamate-Based Inhibitor.
Int J Mol Sci, 22:-, 2021

PubMed 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.

PubMed: 34073350
DOI: 10.3390/ijms22115651

Experimental method

X-RAY DIFFRACTION (2.413 Å)