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| | ==Crystal structure of membrane-type serine protease 1 (MT-SP1) in complex with the Fab Inhibitor S4== | | ==Crystal structure of membrane-type serine protease 1 (MT-SP1) in complex with the Fab Inhibitor S4== |
| - | <StructureSection load='3nps' size='340' side='right' caption='[[3nps]], [[Resolution|resolution]] 1.50Å' scene=''> | + | <StructureSection load='3nps' size='340' side='right'caption='[[3nps]], [[Resolution|resolution]] 1.50Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3nps]] is a 3 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=3NPS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3NPS FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3nps]] is a 3 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=3NPS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3NPS FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</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]] 1.5Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PRSS14, SNC19, ST14, TADG15 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</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'>[https://proteopedia.org/fgij/fg.htm?mol=3nps FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3nps OCA], [https://pdbe.org/3nps PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3nps RCSB], [https://www.ebi.ac.uk/pdbsum/3nps PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3nps ProSAT]</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=3nps FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3nps OCA], [http://pdbe.org/3nps PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3nps RCSB], [http://www.ebi.ac.uk/pdbsum/3nps PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3nps ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == 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 == | | == 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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 3nps" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 3nps" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Matriptase 3D structures|Matriptase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Matriptase]] | + | [[Category: Large Structures]] |
| - | [[Category: Baharuddin, A]] | + | [[Category: Baharuddin A]] |
| - | [[Category: Antibody-protease complex]]
| + | |
| - | [[Category: Disease mutation]]
| + | |
| - | [[Category: Enzyme-inhibitor complex]]
| + | |
| - | [[Category: Glycoprotein]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Hydrolase - immune system complex]]
| + | |
| - | [[Category: Hydrolase-immune system complex]]
| + | |
| - | [[Category: Membrane]]
| + | |
| - | [[Category: Protein-protein complex]]
| + | |
| - | [[Category: Serine protease]]
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| - | [[Category: Signal-anchor]]
| + | |
| - | [[Category: Transmembrane]]
| + | |
| 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 PubMed
The type II transmembrane serine protease family consists of 18 closely related serine proteases that are implicated in multiple functions. To identify selective, inhibitory antibodies against one particular type II transmembrane serine protease, matriptase [MT-SP1 (membrane-type serine protease 1)], a phage display library was created with a natural repertoire of Fabs [fragment antigen binding (Fab)] from human naive B cells. Fab A11 was identified with a 720 pM inhibition constant and high specificity for matriptase over other trypsin-fold serine proteases. A Trichoderma reesei system expressed A11 with a yield of approximately 200 mg/L. The crystal structure of A11 in complex with matriptase has been determined and compared to the crystal structure of another antibody inhibitor (S4) in complex with matriptase. Previously discovered from a synthetic single-chain variable fragment library, S4 is also a highly selective and potent matriptase inhibitor. The crystal structures of the A11/matriptase and S4/matriptase complexes were solved to 2.1 A and 1.5 A, respectively. Although these antibodies, discovered from separate libraries, interact differently with the protease surface loops for their specificity, the structures reveal a similar novel mechanism of protease inhibition. Through the insertion of the H3 variable loop in a reverse orientation at the substrate-binding pocket, these antibodies bury a large surface area for potent inhibition and avoid proteolytic inactivation. This discovery highlights the critical role that the antibody scaffold plays in positioning loops to bind and inhibit protease function in a highly selective manner. Additionally, Fab A11 is a fully human antibody that specifically inhibits matriptase over other closely related proteases, suggesting that this approach could be useful for clinical applications.
A reverse binding motif that contributes to specific protease inhibition by antibodies.,Schneider EL, Lee MS, Baharuddin A, Goetz DH, Farady CJ, Ward M, Wang CI, Craik CS J Mol Biol. 2012 Jan 27;415(4):699-715. Epub 2011 Nov 27. PMID:22154938[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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
- ↑ Schneider EL, Lee MS, Baharuddin A, Goetz DH, Farady CJ, Ward M, Wang CI, Craik CS. A reverse binding motif that contributes to specific protease inhibition by antibodies. J Mol Biol. 2012 Jan 27;415(4):699-715. Epub 2011 Nov 27. PMID:22154938 doi:10.1016/j.jmb.2011.11.036
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