6N4T

Crystal structure of Matriptase1 in complex with a peptidomimetic benzothiazole

Summary for 6N4T

• Entry DOI: 10.2210/pdb6n4t/pdb
• Related PRD ID: PRD_002338
• Descriptor: Suppressor of tumorigenicity 14 protein, MAGNESIUM ION, ETHANOL, ... (7 entities in total)
• Functional Keywords: inhibitor complex, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 27642.46

Authors

Campobasso, N. (deposition date: 2018-11-20, release date: 2019-10-02, Last modification date: 2025-04-02)

Primary citation

Beliveau, F.,Tarkar, A.,Dion, S.P.,Desilets, A.,Ghinet, M.G.,Boudreault, P.L.,St-Georges, C.,Marsault, E.,Paone, D.,Collins, J.,Macphee, C.H.,Campobasso, N.,Groy, A.,Cottom, J.,Ouellette, M.,Pope, A.J.,Leduc, R.
Discovery and Development of TMPRSS6 Inhibitors Modulating Hepcidin Levels in Human Hepatocytes.
Cell Chem Biol, 26:1559-1572.e9, 2019

PubMed Abstract: Iron overload disorders are characterized by the body's inability to regulate iron absorption and its storage which can lead to organ failures. Accumulated evidence has revealed that hepcidin, the master regulator of iron homeostasis, is negatively modulated by TMPRSS6 (matriptase-2), a liver-specific type II transmembrane serine protease (TTSP). Here, we report that treatment with a peptidomimetic inhibitor affecting TMPRSS6 activity increases hepcidin production in hepatic cells. Moreover, similar effects were observed when using non-peptidic inhibitors obtained through optimization of hits from high-throughput screening. Using HepG2 cells and human primary hepatocytes, we show that TMPRSS6 inhibitors block TMPRSS6-dependent hemojuvelin cleavage and increase HAMP expression and levels of secreted hepcidin.

PubMed: 31543462
DOI: 10.1016/j.chembiol.2019.09.004

Experimental method

X-RAY DIFFRACTION (1.945 Å)