7qbo
From Proteopedia
(Difference between revisions)
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==Structure of the activation intermediate of cathepsin K in complex with the azadipeptide nitrile inhibitor Gu1303== | ==Structure of the activation intermediate of cathepsin K in complex with the azadipeptide nitrile inhibitor Gu1303== | ||
| - | <StructureSection load='7qbo' size='340' side='right'caption='[[7qbo]]' scene=''> | + | <StructureSection load='7qbo' size='340' side='right'caption='[[7qbo]], [[Resolution|resolution]] 1.90Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7QBO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7QBO FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7qbo]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7QBO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7QBO FirstGlance]. <br> |
| - | </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=7qbo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7qbo OCA], [https://pdbe.org/7qbo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7qbo RCSB], [https://www.ebi.ac.uk/pdbsum/7qbo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7qbo ProSAT]</span></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9ZG:(phenylmethyl)+~{N}-[(2~{S})-1-[[aminomethyl(methyl)amino]-methyl-amino]-1-oxidanylidene-3-phenyl-propan-2-yl]carbamate'>9ZG</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> |
| + | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Cathepsin_K Cathepsin K], with EC number [https://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'>[https://proteopedia.org/fgij/fg.htm?mol=7qbo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7qbo OCA], [https://pdbe.org/7qbo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7qbo RCSB], [https://www.ebi.ac.uk/pdbsum/7qbo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7qbo ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Disease == | ||
| + | [[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 == | ||
| + | [[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;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Cathepsin K (CatK) is a target for the treatment of osteoporosis, arthritis, and bone metastasis. Peptidomimetics with a cyanohydrazide warhead represent a new class of highly potent CatK inhibitors; however, their binding mechanism is unknown. We investigated two model cyanohydrazide inhibitors with differently positioned warheads: an azadipeptide nitrile Gu1303 and a 3-cyano-3-aza-beta-amino acid Gu2602. Crystal structures of their covalent complexes were determined with mature CatK as well as a zymogen-like activation intermediate of CatK. Binding mode analysis, together with quantum chemical calculations, revealed that the extraordinary picomolar potency of Gu2602 is entropically favoured by its conformational flexibility at the nonprimed-primed subsites boundary. Furthermore, we demonstrated by live cell imaging that cyanohydrazides effectively target mature CatK in osteosarcoma cells. Cyanohydrazides also suppressed the maturation of CatK by inhibiting the autoactivation of the CatK zymogen. Our results provide structural insights for the rational design of cyanohydrazide inhibitors of CatK as potential drugs. | ||
| + | |||
| + | Highly potent inhibitors of cathepsin K with a differently positioned cyanohydrazide warhead: structural analysis of binding mode to mature and zymogen-like enzymes.,Benysek J, Busa M, Rubesova P, Fanfrlik J, Lepsik M, Brynda J, Matouskova Z, Bartz U, Horn M, Gutschow M, Mares M J Enzyme Inhib Med Chem. 2022 Dec;37(1):515-526. doi:, 10.1080/14756366.2021.2024527. PMID:35144520<ref>PMID:35144520</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7qbo" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Cathepsin K]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Benysek J]] | + | [[Category: Benysek, J]] |
| - | [[Category: Busa M]] | + | [[Category: Busa, M]] |
| - | [[Category: Mares M]] | + | [[Category: Mares, M]] |
| + | [[Category: Azadipeptide nitrile]] | ||
| + | [[Category: Cathepsin k]] | ||
| + | [[Category: Cyanohydrazide warhead]] | ||
| + | [[Category: Hydrolase]] | ||
| + | [[Category: Protease inhibitor]] | ||
Revision as of 08:43, 23 February 2022
Structure of the activation intermediate of cathepsin K in complex with the azadipeptide nitrile inhibitor Gu1303
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