4r0i: Difference between revisions
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==CRYSTAL STRUCTURE of MATRIPTASE in COMPLEX WITH INHIBITOR== | |||
<StructureSection load='4r0i' size='340' side='right'caption='[[4r0i]], [[Resolution|resolution]] 1.90Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4r0i]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4R0I OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4R0I FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3KM:3-({(2S)-3-[4-(2-AMINOETHYL)PIPERIDIN-1-YL]-2-[(NAPHTHALEN-2-YLSULFONYL)AMINO]-3-OXOPROPYL}OXY)BENZENECARBOXIMIDAMIDE'>3KM</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4r0i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r0i OCA], [https://pdbe.org/4r0i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4r0i RCSB], [https://www.ebi.ac.uk/pdbsum/4r0i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4r0i ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[https://www.uniprot.org/uniprot/ST14_HUMAN ST14_HUMAN] Defects in ST14 are a cause of ichthyosis autosomal recessive with hypotrichosis (ARIH) [MIM:[https://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 == | |||
[https://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 == | |||
Matriptase is a cell-surface trypsin-like serine protease of epithelial origin, which cleaves and activates proteins including hepatocyte growth factor/scatter factor and proteases such as uPA, which are involved in the progression of various cancers. Here we report a fragment-linking approach, which led to the discovery of O-(3-carbamimidoylphenyl)-l-serine amides as potent matriptase inhibitors. The co-crystal structure of one of the potent inhibitors, 6 in complex with matriptase catalytic domain validated the working hypothesis guiding the development of this congeneric series and revealed the structural basis for matriptase inhibition. Replacement of a naphthyl group in 6 with 2,4,6-tri-isopropyl phenyl resulted in 10 with improved matriptase inhibition, which exhibited significant primary tumor growth inhibition in a mouse model of prostate cancer. Compounds such as 10, identified using a fragment-linking approach, can be explored further to understand the role of matriptase as a drug target in cancer and inflammation. | |||
Discovery of O-(3-carbamimidoylphenyl)-l-serine amides as matriptase inhibitors using a fragment-linking approach.,Goswami R, Wohlfahrt G, Mukherjee S, Ghadiyaram C, Nagaraj J, Satyam LK, Subbarao K, Gopinath S, Krishnamurthy NR, Subramanya HS, Ramachandra M Bioorg Med Chem Lett. 2015 Feb 1;25(3):616-20. doi: 10.1016/j.bmcl.2014.12.008., Epub 2014 Dec 17. PMID:25556099<ref>PMID:25556099</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4r0i" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Matriptase 3D structures|Matriptase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Ashok KN]] | |||
[[Category: Chakshusmathi G]] | |||
[[Category: Rajeev G]] | |||
[[Category: Rao KN]] | |||
[[Category: Subramanya H]] | |||
