6qbs
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | The | + | ==The Alkyne Moiety as a Latent Electrophile in Irreversible Covalent Small Molecule Inhibitors of Cathepsin K== |
| + | <StructureSection load='6qbs' size='340' side='right' caption='[[6qbs]], [[Resolution|resolution]] 1.70Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[6qbs]] is a 2 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=6QBS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6QBS FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=HVW:(2~{S})-4-methyl-~{N}-prop-2-enyl-2-[[(1~{S})-2,2,2-tris(fluoranyl)-1-[4-(4-methylsulfonylphenyl)phenyl]ethyl]amino]pentanamide'>HVW</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='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=6qbs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6qbs OCA], [http://pdbe.org/6qbs PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6qbs RCSB], [http://www.ebi.ac.uk/pdbsum/6qbs PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6qbs 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 == | ||
| + | Irreversible covalent inhibitors can have a beneficial pharmacokinetic/pharmacodynamics profile but are still often avoided due to the risk of indiscriminate covalent reactivity and the resulting adverse effects. To overcome this potential liability, we introduced an alkyne moiety as a latent electrophile into small molecule inhibitors of cathepsin K (CatK). Alkyne-based inhibitors do not show indiscriminate thiol reactivity but potently inhibit CatK protease activity by formation of an irreversible covalent bond with the catalytic cysteine residue, confirmed by crystal structure analysis. The rate of covalent bond formation ( kinact) does not correlate with electrophilicity of the alkyne moiety, indicative of a proximity-driven reactivity. Inhibition of CatK-mediated bone resorption is validated in human osteoclasts. Together, this work illustrates the potential of alkynes as latent electrophiles in small molecule inhibitors, enabling the development of irreversible covalent inhibitors with an improved safety profile. | ||
| - | + | The Alkyne Moiety as a Latent Electrophile in Irreversible Covalent Small Molecule Inhibitors of Cathepsin K.,Mons E, Jansen IDC, Loboda J, van Doodewaerd BR, Hermans J, Verdoes M, van Boeckel CAA, van Veelen PA, Turk B, Turk D, Ovaa H J Am Chem Soc. 2019 Feb 27;141(8):3507-3514. doi: 10.1021/jacs.8b11027. Epub 2019, Feb 14. PMID:30689386<ref>PMID:30689386</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 6qbs" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Cathepsin K]] | ||
| + | [[Category: Human]] | ||
| + | [[Category: Boeckel, C A.A van]] | ||
| + | [[Category: Doodewaerd, B R.van]] | ||
[[Category: Hermans, J]] | [[Category: Hermans, J]] | ||
| - | [[Category: | + | [[Category: Jansen, I D.C]] |
| - | [[Category: | + | [[Category: Loboda, J]] |
[[Category: Mons, E]] | [[Category: Mons, E]] | ||
| + | [[Category: Ovaa, H]] | ||
[[Category: Turk, B]] | [[Category: Turk, B]] | ||
| - | [[Category: Jansen, I.D.C]] | ||
[[Category: Turk, D]] | [[Category: Turk, D]] | ||
| - | [[Category: | + | [[Category: Veelen, P A.van]] |
| - | [[Category: | + | [[Category: Verdoes, M]] |
| - | [[Category: | + | [[Category: Cathepsin k]] |
| - | [[Category: | + | [[Category: Covalent inhibitor]] |
| + | [[Category: Hydrolase]] | ||
Revision as of 08:33, 6 March 2019
The Alkyne Moiety as a Latent Electrophile in Irreversible Covalent Small Molecule Inhibitors of Cathepsin K
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Categories: Cathepsin K | Human | Boeckel, C A.A van | Doodewaerd, B R.van | Hermans, J | Jansen, I D.C | Loboda, J | Mons, E | Ovaa, H | Turk, B | Turk, D | Veelen, P A.van | Verdoes, M | Cathepsin k | Covalent inhibitor | Hydrolase
