Structural Studies on the Inhibitory Binding Mode of Aromatic Coumarinic Esters to Human Kallikrein-Related Peptidase 7

• Published in: Journal of medicinal chemistry Vol. 63; no. 11; pp. 5723 - 5733
• Main Authors: Hanke, Stefanie, Tindall, Catherine A, Pippel, Jan, Ulbricht, David, Pirotte, Bernard, Reboud-Ravaux, Michèle, Heiker, John T, Sträter, Norbert
• Format: Journal Article Web Resource
• Language: English
• Published: United States American Chemical Society 11-06-2020
• Subjects: Binding Sites; Catalytic Domain; coumarin; Coumarins; Coumarins/chemistry; Coumarins/metabolism; Crystallography, X-Ray; Drug Discovery; Esters; Esters/chemistry; Human health sciences; Humans; Kallikreins; Kallikreins/antagonists & inhibitors; Kallikreins/genetics; Kallikreins/metabolism; KLK7 protein, human; Molecular Dynamics Simulation; Molecular Medicine; Pharmacie, pharmacologie & toxicologie; Pharmacy, pharmacology & toxicology; Protease Inhibitors; Protease Inhibitors/chemistry; Protease Inhibitors/metabolism; Recombinant Proteins; Recombinant Proteins/biosynthesis; Recombinant Proteins/chemistry; Recombinant Proteins/isolation & purification; Sciences de la santé humaine; Tandem Mass Spectrometry
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.9b01806

The 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 the hydrolysis of the ester linkage. With these results, we analyze the structural basis of KLK7 inhibition by the covalent attachment of aromatic coumarinic esters.