7aq1 | pdb_00007aq1

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

spinqualitylabelsall models 7aq1, resolution 2.41Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7aq1 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: BMA, CA, CL, EDO, NAG, RUE, ZN, MAN Gene: MEP1B (HUMAN) Activity: Meprin B, with EC number 3.4.24.63 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [MEP1B_HUMAN] Membrane metallopeptidase that sheds many membrane-bound proteins. Known substrates include: FGF19, VGFA, IL1B, IL18, procollagen I and III, E-cadherin, KLK7, gastrin, ADAM10, tenascin-C. The presence of several pro-inflammatory cytokine among substrates implicate MEP1B in inflammation. It is also involved in tissue remodeling due to its capability to degrade extracellular matrix components. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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