6SHI

Human kallikrein 7 with aromatic coumarinic ester compound 2 covalently bound to H57

6SHI の概要

• エントリーDOI: 10.2210/pdb6shi/pdb
• 分子名称: Kallikrein-7, TRIETHYLENE GLYCOL, 6-methyl-2-oxidanylidene-chromene-3-carboxylic acid, ... (6 entities in total)
• 機能のキーワード: serine protease, covalent inhibitor, complex, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 206917.49

構造登録者

Hanke, S.,Straeter, N. (登録日: 2019-08-06, 公開日: 2020-05-20, 最終更新日: 2024-10-16)

主引用文献

Hanke, S.,Tindall, C.A.,Pippel, J.,Ulbricht, D.,Pirotte, B.,Reboud-Ravaux, M.,Heiker, J.T.,Strater, N.
Structural Studies on the Inhibitory Binding Mode of Aromatic Coumarinic Esters to Human Kallikrein-Related Peptidase 7.
J.Med.Chem., 63:5723-5733, 2020

PubMed Abstract: 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.

PubMed: 32374603
DOI: 10.1021/acs.jmedchem.9b01806

実験手法

X-RAY DIFFRACTION (1.85 Å)