7qbl: Difference between revisions

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<StructureSection load='7qbl' size='340' side='right'caption='[[7qbl]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
<StructureSection load='7qbl' size='340' side='right'caption='[[7qbl]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[7qbl]] 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=7QBL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7QBL FirstGlance]. <br>
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7QBL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7QBL 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&#8491;</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]] 2&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A0U:~{tert}-butyl+~{N}-[iminomethyl-[2-[methyl-(phenylmethyl)amino]-2-oxidanylidene-ethyl]amino]carbamate'>A0U</scene></td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A0U:~{tert}-butyl+~{N}-[iminomethyl-[2-[methyl-(phenylmethyl)amino]-2-oxidanylidene-ethyl]amino]carbamate'>A0U</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=7qbl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7qbl OCA], [https://pdbe.org/7qbl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7qbl RCSB], [https://www.ebi.ac.uk/pdbsum/7qbl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7qbl 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=7qbl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7qbl OCA], [https://pdbe.org/7qbl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7qbl RCSB], [https://www.ebi.ac.uk/pdbsum/7qbl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7qbl 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&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7qbl" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Benysek J]]
[[Category: Benysek J]]
[[Category: Busa M]]
[[Category: Busa M]]
[[Category: Mares M]]
[[Category: Mares M]]

Latest revision as of 12:06, 17 October 2024

Structure of cathepsin K in complex with the 3-cyano-3-aza-beta-amino acid inhibitor Gu2602Structure of cathepsin K in complex with the 3-cyano-3-aza-beta-amino acid inhibitor Gu2602

Structural highlights

Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

7qbl, resolution 2.00Å

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