Structural highlights
Publication Abstract from PubMedThe serine protease kallikrein-related peptidase 7 (KLK7) is a member of the human tissue kallikreins. Its dysregulation leads to pathophysiological inflammatory processes in the skin. Furthermore, it plays a role in several types of cancer. For the treatment of KLK7-associated diseases, coumarinic esters have been developed as small molecule enzyme inhibitors. To characterize the inhibition mode of these inhibitors, we analyzed structures of the inhibited protease by X-ray crystallography. Electron density shows the inhibitors covalently attached to His57 of the catalytic triad. This confirms the irreversible character of the inhibition process. Upon inhibitor binding His57 undergoes an outward rotation thus the catalytic triad of the protease is disrupted. Besides, the halophenyl moiety of the inhibitor was absent in the final enzyme-inhibitor complex due to hydrolysis of the ester linkage. With these results, we analyze the structural basis of KLK7 inhibition by covalent attachment of aromatic coumarinic esters. Structural studies on the inhibitory binding mode of aromatic coumarinic esters to human kallikrein-related peptidase 7.,Hanke S, Tindall C, Pippel J, Ulbricht D, Pirotte B, Reboud-Ravaux M, Heiker JT, Strater N J Med Chem. 2020 May 6. doi: 10.1021/acs.jmedchem.9b01806. PMID:32374603[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
| ||||||||||||||||||||
This page was last modified 05:47, 21 November 2024.