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4r0i

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CRYSTAL STRUCTURE of MATRIPTASE in COMPLEX WITH INHIBITOR

Structural highlights

4r0i is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.9Å
Ligands:
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 See Also
6 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=''>
+<StructureSection load='4r0i' size='340' side='right'caption='[[4r0i]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4r0i]] is a 2 chain structure. 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 [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4R0I FirstGlance]. <br>
+<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='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>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9&#8491;</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='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'>[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'>[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 ==
-[[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>
+[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 ==
-[[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.
+[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 ==
@@ 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>
+==See Also==
+*[[Matriptase 3D structures|Matriptase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Matriptase]]
+[[Category: Homo sapiens]]
-[[Category: Ashok, K N]]
+[[Category: Large Structures]]
-[[Category: Chakshusmathi, G]]
+[[Category: Ashok KN]]
-[[Category: Rajeev, G]]
+[[Category: Chakshusmathi G]]
-[[Category: Rao, K N]]
+[[Category: Rajeev G]]
-[[Category: Subramanya, H]]
+[[Category: Rao KN]]
-[[Category: Complex structure]]
+[[Category: Subramanya H]]
-[[Category: Hydrolase]]
-[[Category: Protease]]
-[[Category: Small molecule inhibitor]]
-[[Category: Trypsin-like serine proteinase fold]]

4r0i

From Proteopedia

Current revision

CRYSTAL STRUCTURE of MATRIPTASE in COMPLEX WITH INHIBITOR

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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