6n4t: Difference between revisions
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==Crystal structure of Matriptase1 in complex with a peptidomimetic benzothiazole== | |||
<StructureSection load='6n4t' size='340' side='right'caption='[[6n4t]], [[Resolution|resolution]] 1.94Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6n4t]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6N4T OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6N4T FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=144:TRIS-HYDROXYMETHYL-METHYL-AMMONIUM'>144</scene>, <scene name='pdbligand=EOH:ETHANOL'>EOH</scene>, <scene name='pdbligand=GSH:GLUTATHIONE'>GSH</scene>, <scene name='pdbligand=KD7:N-(3-phenylpropanoyl)-3-(1,3-thiazol-4-yl)-L-alanyl-N-[(1S,2S)-1-(1,3-benzothiazol-2-yl)-5-carbamimidamido-1-hydroxypentan-2-yl]-L-valinamide'>KD7</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ST14, PRSS14, SNC19, TADG15 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Matriptase Matriptase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.109 3.4.21.109] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6n4t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6n4t OCA], [http://pdbe.org/6n4t PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6n4t RCSB], [http://www.ebi.ac.uk/pdbsum/6n4t PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6n4t ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[[http://www.uniprot.org/uniprot/ST14_HUMAN ST14_HUMAN]] Defects in ST14 are a cause of ichthyosis autosomal recessive with hypotrichosis (ARIH) [MIM:[http://omim.org/entry/610765 610765]]. ARIH is a skin disorder characterized by congenital ichthyosis associated with the presence of less than the normal amount of hair.<ref>PMID:17273967</ref> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/ST14_HUMAN 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. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
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. | |||
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<ref>PMID:31543462</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6n4t" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Matriptase 3D structures|Matriptase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Human]] | |||
[[Category: Large Structures]] | |||
[[Category: Matriptase]] | |||
[[Category: Campobasso, N]] | [[Category: Campobasso, N]] | ||
[[Category: Hydrolase]] | |||
[[Category: Hydrolase-hydrolase inhibitor complex]] | |||
[[Category: Inhibitor complex]] | |||
Latest revision as of 13:29, 4 December 2019
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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