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| | ==Cathepsin K in complex with a covalent inhibitor with a ketoamide warhead== | | ==Cathepsin K in complex with a covalent inhibitor with a ketoamide warhead== |
| - | <StructureSection load='3ovz' size='340' side='right' caption='[[3ovz]], [[Resolution|resolution]] 2.02Å' scene=''> | + | <StructureSection load='3ovz' size='340' side='right'caption='[[3ovz]], [[Resolution|resolution]] 2.02Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3ovz]] 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=3OVZ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3OVZ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3ovz]] is a 1 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=3OVZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3OVZ FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=O96:N-[(1S)-3-AMINO-1-ETHYL-2,3-DIOXOPROPYL]-2-CHLORO-4-(PYRIDIN-2-YLMETHOXY)-3-(TRIFLUOROMETHYL)BENZAMIDE'>O96</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 2.02Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3ovx|3ovx]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=O96:N-[(1S)-3-AMINO-1-ETHYL-2,3-DIOXOPROPYL]-2-CHLORO-4-(PYRIDIN-2-YLMETHOXY)-3-(TRIFLUOROMETHYL)BENZAMIDE'>O96</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CTSK, CTSO, CTSO2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=3ovz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ovz OCA], [https://pdbe.org/3ovz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3ovz RCSB], [https://www.ebi.ac.uk/pdbsum/3ovz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3ovz ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Cathepsin_K Cathepsin K], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.38 3.4.22.38] </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=3ovz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ovz OCA], [http://pdbe.org/3ovz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3ovz RCSB], [http://www.ebi.ac.uk/pdbsum/3ovz PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3ovz ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/CATK_HUMAN CATK_HUMAN]] Defects in CTSK are the cause of pycnodysostosis (PKND) [MIM:[http://omim.org/entry/265800 265800]]. PKND is an autosomal recessive osteochondrodysplasia characterized by osteosclerosis and short stature.<ref>PMID:8703060</ref> <ref>PMID:9529353</ref> <ref>PMID:10491211</ref> <ref>PMID:10878663</ref> | + | [https://www.uniprot.org/uniprot/CATK_HUMAN CATK_HUMAN] Defects in CTSK are the cause of pycnodysostosis (PKND) [MIM:[https://omim.org/entry/265800 265800]. PKND is an autosomal recessive osteochondrodysplasia characterized by osteosclerosis and short stature.<ref>PMID:8703060</ref> <ref>PMID:9529353</ref> <ref>PMID:10491211</ref> <ref>PMID:10878663</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CATK_HUMAN CATK_HUMAN]] Closely involved in osteoclastic bone resorption and may participate partially in the disorder of bone remodeling. Displays potent endoprotease activity against fibrinogen at acid pH. May play an important role in extracellular matrix degradation. | + | [https://www.uniprot.org/uniprot/CATK_HUMAN CATK_HUMAN] Closely involved in osteoclastic bone resorption and may participate partially in the disorder of bone remodeling. Displays potent endoprotease activity against fibrinogen at acid pH. May play an important role in extracellular matrix degradation. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| - | *[[Cathepsin|Cathepsin]] | + | *[[Cathepsin 3D structures|Cathepsin 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Cathepsin K]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]] | + | [[Category: Large Structures]] |
| - | [[Category: Fradera, X]] | + | [[Category: Fradera X]] |
| - | [[Category: Uitdehaag, J C.M]] | + | [[Category: Uitdehaag JCM]] |
| - | [[Category: Zeeland, M van]] | + | [[Category: Van Zeeland M]] |
| - | [[Category: Cathepsin k]]
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| - | [[Category: Covalent inhibitor]]
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| - | [[Category: Hydrolase]]
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| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
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| - | [[Category: Ketoamide warhead]]
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| - | [[Category: Ligand forms covalent bond to cys25]]
| + | |
| - | [[Category: Lysosome]]
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| Structural highlights
Disease
CATK_HUMAN Defects in CTSK are the cause of pycnodysostosis (PKND) [MIM:265800. PKND is an autosomal recessive osteochondrodysplasia characterized by osteosclerosis and short stature.[1] [2] [3] [4]
Function
CATK_HUMAN Closely involved in osteoclastic bone resorption and may participate partially in the disorder of bone remodeling. Displays potent endoprotease activity against fibrinogen at acid pH. May play an important role in extracellular matrix degradation.
Publication Abstract from PubMed
The trifluoromethylphenyl P2 motif from previously reported heteroarylnitrile series has been successfully applied for the design and synthesis of highly potent novel ketoamide-based cathepsin S inhibitors. The key in this process is the change of the torsion angle between the P2 phenyl ring and the attached secondary amide by adding a small Cl, F, or Me group at the 2-position.
Trifluoromethylphenyl as P2 for ketoamide-based cathepsin S inhibitors.,Cai J, Robinson J, Belshaw S, Everett K, Fradera X, van Zeeland M, van Berkom L, van Rijnsbergen P, Popplestone L, Baugh M, Dempster M, Bruin J, Hamilton W, Kinghorn E, Westwood P, Kerr J, Rankovic Z, Arbuckle W, Bennett DJ, Jones PS, Long C, Martin I, Uitdehaag JC, Meulemans T Bioorg Med Chem Lett. 2010 Dec 1;20(23):6890-4. Epub 2010 Oct 26. PMID:21030256[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Gelb BD, Shi GP, Chapman HA, Desnick RJ. Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science. 1996 Aug 30;273(5279):1236-8. PMID:8703060
- ↑ Gelb BD, Willner JP, Dunn TM, Kardon NB, Verloes A, Poncin J, Desnick RJ. Paternal uniparental disomy for chromosome 1 revealed by molecular analysis of a patient with pycnodysostosis. Am J Hum Genet. 1998 Apr;62(4):848-54. PMID:9529353 doi:S0002-9297(07)60977-X
- ↑ Ho N, Punturieri A, Wilkin D, Szabo J, Johnson M, Whaley J, Davis J, Clark A, Weiss S, Francomano C. Mutations of CTSK result in pycnodysostosis via a reduction in cathepsin K protein. J Bone Miner Res. 1999 Oct;14(10):1649-53. PMID:10491211
- ↑ Haagerup A, Hertz JM, Christensen MF, Binderup H, Kruse TA. Cathepsin K gene mutations and 1q21 haplotypes in at patients with pycnodysostosis in an outbred population. Eur J Hum Genet. 2000 Jun;8(6):431-6. PMID:10878663 doi:10.1038/sj.ejhg.5200481
- ↑ Cai J, Robinson J, Belshaw S, Everett K, Fradera X, van Zeeland M, van Berkom L, van Rijnsbergen P, Popplestone L, Baugh M, Dempster M, Bruin J, Hamilton W, Kinghorn E, Westwood P, Kerr J, Rankovic Z, Arbuckle W, Bennett DJ, Jones PS, Long C, Martin I, Uitdehaag JC, Meulemans T. Trifluoromethylphenyl as P2 for ketoamide-based cathepsin S inhibitors. Bioorg Med Chem Lett. 2010 Dec 1;20(23):6890-4. Epub 2010 Oct 26. PMID:21030256 doi:10.1016/j.bmcl.2010.10.012
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