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4r0i

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Revision as of 17:21, 18 January 2017

CRYSTAL STRUCTURE of MATRIPTASE in COMPLEX WITH INHIBITOR

Structural highlights

4r0i is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Activity:	Matriptase, with EC number 3.4.21.109
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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 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^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Basel-Vanagaite L, Attia R, Ishida-Yamamoto A, Rainshtein L, Ben Amitai D, Lurie R, Pasmanik-Chor M, Indelman M, Zvulunov A, Saban S, Magal N, Sprecher E, Shohat M. Autosomal recessive ichthyosis with hypotrichosis caused by a mutation in ST14, encoding type II transmembrane serine protease matriptase. Am J Hum Genet. 2007 Mar;80(3):467-77. Epub 2007 Jan 23. PMID:17273967 doi:S0002-9297(07)60095-0
↑ Goswami R, Wohlfahrt G, Mukherjee S, Ghadiyaram C, Nagaraj J, Satyam LK, Subbarao K, Gopinath S, Krishnamurthy NR, Subramanya HS, Ramachandra M. Discovery of O-(3-carbamimidoylphenyl)-l-serine amides as matriptase inhibitors using a fragment-linking approach. 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 doi:http://dx.doi.org/10.1016/j.bmcl.2014.12.008

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4r0i"

@@ Line 1: / Line 1: @@
 ==CRYSTAL STRUCTURE of MATRIPTASE in COMPLEX WITH INHIBITOR==
 <StructureSection load='4r0i' size='340' side='right' caption='[[4r0i]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
@@ Line 5: / Line 6: @@
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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='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=4r0i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r0i OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4r0i RCSB], [http://www.ebi.ac.uk/pdbsum/4r0i PDBsum]</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=4r0i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r0i OCA], [http://pdbe.org/4r0i PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4r0i RCSB], [http://www.ebi.ac.uk/pdbsum/4r0i PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4r0i ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 19: / Line 20: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4r0i" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>

4r0i

From Proteopedia

Revision as of 17:21, 18 January 2017

CRYSTAL STRUCTURE of MATRIPTASE in COMPLEX WITH INHIBITOR

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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