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| - | ==Crystal stucture of Cathepsin K with a covalently-linked inhibitor at 1.4 Angstrom resolution.== | + | ==Crystal structure of Cathepsin K with a covalently-linked inhibitor at 1.4 Angstrom resolution.== |
| - | <StructureSection load='5tdi' size='340' side='right' caption='[[5tdi]], [[Resolution|resolution]] 1.40Å' scene=''> | + | <StructureSection load='5tdi' size='340' side='right'caption='[[5tdi]], [[Resolution|resolution]] 1.40Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5tdi]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TDI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5TDI FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5tdi]] 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=5TDI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5TDI FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7AS:4-FLUORO-N-{1-[(Z)-IMINOMETHYL]CYCLOPROPYL}-N~2~-{(1S)-2,2,2-TRIFLUORO-1-[4-(METHYLSULFONYL)[1,1-BIPHENYL]-4-YL]ETHYL}-L-LEUCINAMIDE'>7AS</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]] 1.4Å</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7AS:4-FLUORO-N-{1-[(Z)-IMINOMETHYL]CYCLOPROPYL}-N~2~-{(1S)-2,2,2-TRIFLUORO-1-[4-(METHYLSULFONYL)[1,1-BIPHENYL]-4-YL]ETHYL}-L-LEUCINAMIDE'>7AS</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=5tdi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tdi OCA], [http://pdbe.org/5tdi PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5tdi RCSB], [http://www.ebi.ac.uk/pdbsum/5tdi PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5tdi ProSAT]</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=5tdi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tdi OCA], [https://pdbe.org/5tdi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5tdi RCSB], [https://www.ebi.ac.uk/pdbsum/5tdi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5tdi 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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| | </div> | | </div> |
| | <div class="pdbe-citations 5tdi" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5tdi" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Cathepsin 3D structures|Cathepsin 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Cathepsin K]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Aguda, A]] | + | [[Category: Large Structures]] |
| - | [[Category: Brayer, G]] | + | [[Category: Aguda A]] |
| - | [[Category: Bromme, D]] | + | [[Category: Brayer G]] |
| - | [[Category: Law, S]] | + | [[Category: Bromme D]] |
| - | [[Category: Nguyen, N]] | + | [[Category: Law S]] |
| - | [[Category: Cathepsin k]]
| + | [[Category: Nguyen N]] |
| - | [[Category: Covalent]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| 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
Cathepsin K (CatK) is the predominant mammalian bone-degrading protease and thus an ideal target for anti-osteoporotic drug development. Rodent models of osteoporosis are preferred due to their close reflection of the human disease and their ease of handling, genetic manipulation, and economic affordability. However, large differences in the potency of CatK inhibitors for the mouse/rat versus the human protease orthologues have made it impossible to use rodent models. This is even more of a problem considering that the most advanced CatK inhibitors including odanacatib and balicatib failed in human clinical trials due to side effects and rodent models are not available to investigate the mechanism of these failures. Here, we elucidated the structural elements of the potency differences between mouse and human CatK using odanacatib (ODN). We determined and compared the structures of inhibitor-free mouse CatK (mCatK), human CatK (hCatK) and ODN bound to hCatK. Two structural differences were identified and investigated by mutational analysis. Humanizing subsite 2 in mCatK led to a 5-fold improvement of ODN binding whereas the replacement of Tyr61 in mCatK with Asp resulted in an hCatK with comparable ODN potency. Combining both sites further improved the inhibition of the mCatK variant. Similar results were obtained for balicatib. These findings will allow the generation of transgenic CatK mice that will facilitate the evaluation of CatK inhibitor adverse effects and to explore routes to avoid them.
Identification of mouse cathepsin K structural elements that regulate the potency of odanacatib.,Law S, Andrault PM, Aguda A, Nguyen N, Kruglyak N, Brayer G, Bromme D Biochem J. 2017 Jan 3. pii: BCJ20160985. doi: 10.1042/BCJ20160985. PMID:28049758[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
- ↑ Law S, Andrault PM, Aguda A, Nguyen N, Kruglyak N, Brayer G, Bromme D. Identification of mouse cathepsin K structural elements that regulate the potency of odanacatib. Biochem J. 2017 Jan 3. pii: BCJ20160985. doi: 10.1042/BCJ20160985. PMID:28049758 doi:http://dx.doi.org/10.1042/BCJ20160985
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