5t6u: Difference between revisions
m Protected "5t6u" [edit=sysop:move=sysop] |
No edit summary |
||
| (4 intermediate revisions by the same user not shown) | |||
| Line 1: | Line 1: | ||
==Crystal structure of mouse cathepsin K at 2.9 Angstroms resolution.== | |||
<StructureSection load='5t6u' size='340' side='right'caption='[[5t6u]], [[Resolution|resolution]] 2.90Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5t6u]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5T6U OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5T6U FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.9Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=5t6u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5t6u OCA], [https://pdbe.org/5t6u PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5t6u RCSB], [https://www.ebi.ac.uk/pdbsum/5t6u PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5t6u ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/CATK_MOUSE CATK_MOUSE] 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 (By similarity). | |||
<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> | ||
[[Category: | <div class="pdbe-citations 5t6u" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Cathepsin 3D structures|Cathepsin 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Mus musculus]] | |||
[[Category: Aguda A]] | |||
[[Category: Brayer G]] | |||
[[Category: Bromme D]] | |||
[[Category: Law S]] | |||
[[Category: Nguyen N]] | |||
Latest revision as of 15:55, 4 October 2023
Crystal structure of mouse cathepsin K at 2.9 Angstroms resolution.Crystal structure of mouse cathepsin K at 2.9 Angstroms resolution.
Structural highlights
FunctionCATK_MOUSE 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 (By similarity). 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||