5tun: Difference between revisions
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==Crystal stucture of uninhibited human Cathepsin K at 1.62 Angstrom resolution== | |||
<StructureSection load='5tun' size='340' side='right' caption='[[5tun]], [[Resolution|resolution]] 1.62Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5tun]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TUN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5TUN FirstGlance]. <br> | |||
</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=5tun FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tun OCA], [http://pdbe.org/5tun PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5tun RCSB], [http://www.ebi.ac.uk/pdbsum/5tun PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5tun ProSAT]</span></td></tr> | |||
</table> | |||
== 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> | |||
== 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. | |||
<div style="background-color:#fffaf0;"> | |||
== 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<ref>PMID:28049758</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 5tun" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Cathepsin K]] | |||
[[Category: Aguda, A H]] | |||
[[Category: Brayer, G D]] | |||
[[Category: Bromme, D]] | [[Category: Bromme, D]] | ||
[[Category: Kruglyak, N]] | |||
[[Category: Law, S]] | [[Category: Law, S]] | ||
[[Category: Nguyen, N T]] | |||
[[Category: Nguyen, N | [[Category: Cathepsin k]] | ||
[[Category: | [[Category: Hydrolase]] | ||
[[Category: | |||
Revision as of 19:10, 18 January 2017
Crystal stucture of uninhibited human Cathepsin K at 1.62 Angstrom resolutionCrystal stucture of uninhibited human Cathepsin K at 1.62 Angstrom resolution
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 PubMedCathepsin 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. References
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