6n4t
Crystal structure of Matriptase1 in complex with a peptidomimetic benzothiazoleCrystal structure of Matriptase1 in complex with a peptidomimetic benzothiazole
Structural highlights
Disease[ST14_HUMAN] Defects in ST14 are a cause of ichthyosis autosomal recessive with hypotrichosis (ARIH) [MIM:610765]. ARIH is a skin disorder characterized by congenital ichthyosis associated with the presence of less than the normal amount of hair.[1] Function[ST14_HUMAN] Degrades extracellular matrix. Proposed to play a role in breast cancer invasion and metastasis. Exhibits trypsin-like activity as defined by cleavage of synthetic substrates with Arg or Lys as the P1 site. Publication Abstract from PubMedIron 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. Discovery and Development of TMPRSS6 Inhibitors Modulating Hepcidin Levels in Human Hepatocytes.,Beliveau F, Tarkar A, Dion SP, Desilets A, Ghinet MG, Boudreault PL, St-Georges C, Marsault E, Paone D, Collins J, Macphee CH, Campobasso N, Groy A, Cottom J, Ouellette M, Pope AJ, Leduc R Cell Chem Biol. 2019 Sep 17. pii: S2451-9456(19)30278-8. doi:, 10.1016/j.chembiol.2019.09.004. PMID:31543462[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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