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| | <StructureSection load='2bdl' size='340' side='right'caption='[[2bdl]], [[Resolution|resolution]] 2.00Å' scene=''> | | <StructureSection load='2bdl' size='340' side='right'caption='[[2bdl]], [[Resolution|resolution]] 2.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2bdl]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2BDL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2BDL FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2bdl]] 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=2BDL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2BDL FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4PR:(3S)-1-{[(3,5-DIMETHYLISOXAZOL-4-YL)AMINO]CARBONYL}-4,4-DIMETHYLPYRROLIDIN-3-YL{(1S)-1-[1-HYDROXY-2-OXO-2-{[(1R)-1-PHENYLETHYL]AMINO}ETHYL]PENTYL}CARBAMATE'>4PR</scene></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]] 2Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CTSK, CTSO, CTSO2 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4PR:(3S)-1-{[(3,5-DIMETHYLISOXAZOL-4-YL)AMINO]CARBONYL}-4,4-DIMETHYLPYRROLIDIN-3-YL{(1S)-1-[1-HYDROXY-2-OXO-2-{[(1R)-1-PHENYLETHYL]AMINO}ETHYL]PENTYL}CARBAMATE'>4PR</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=2bdl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2bdl OCA], [https://pdbe.org/2bdl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2bdl RCSB], [https://www.ebi.ac.uk/pdbsum/2bdl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2bdl 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=2bdl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2bdl OCA], [https://pdbe.org/2bdl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2bdl RCSB], [https://www.ebi.ac.uk/pdbsum/2bdl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2bdl ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == 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>
| + | [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 == | | == 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.
| + | [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. |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Cathepsin K]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]]
| + | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Shewchuk, L M]] | + | [[Category: Shewchuk LM]] |
| - | [[Category: Cathepsin]]
| + | |
| - | [[Category: Catk]]
| + | |
| - | [[Category: Cato]]
| + | |
| - | [[Category: Cysteine protease]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| 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.
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Starting from a potent pantolactone ketoamide cathepsin K inhibitor discovered from structural screening, conversion of the lactone scaffold to a pyrrolidine scaffold allowed exploration of the S(3) subsite of cathepsin K. Manipulation of P3 and P1' groups afforded potent inhibitors with drug-like properties.
Novel, potent P2-P3 pyrrolidine derivatives of ketoamide-based cathepsin K inhibitors.,Barrett DG, Catalano JG, Deaton DN, Hassell AM, Long ST, Miller AB, Miller LR, Ray JA, Samano V, Shewchuk LM, Wells-Knecht KJ, Willard DH Jr, Wright LL Bioorg Med Chem Lett. 2006 Mar 15;16(6):1735-9. Epub 2006 Jan 11. PMID:16376075[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Gelb BD, Shi GP, Chapman HA, Desnick RJ. Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science. 1996 Aug 30;273(5279):1236-8. PMID:8703060
- ↑ Gelb BD, Willner JP, Dunn TM, Kardon NB, Verloes A, Poncin J, Desnick RJ. Paternal uniparental disomy for chromosome 1 revealed by molecular analysis of a patient with pycnodysostosis. Am J Hum Genet. 1998 Apr;62(4):848-54. PMID:9529353 doi:S0002-9297(07)60977-X
- ↑ Ho N, Punturieri A, Wilkin D, Szabo J, Johnson M, Whaley J, Davis J, Clark A, Weiss S, Francomano C. Mutations of CTSK result in pycnodysostosis via a reduction in cathepsin K protein. J Bone Miner Res. 1999 Oct;14(10):1649-53. PMID:10491211
- ↑ Haagerup A, Hertz JM, Christensen MF, Binderup H, Kruse TA. Cathepsin K gene mutations and 1q21 haplotypes in at patients with pycnodysostosis in an outbred population. Eur J Hum Genet. 2000 Jun;8(6):431-6. PMID:10878663 doi:10.1038/sj.ejhg.5200481
- ↑ Barrett DG, Catalano JG, Deaton DN, Hassell AM, Long ST, Miller AB, Miller LR, Ray JA, Samano V, Shewchuk LM, Wells-Knecht KJ, Willard DH Jr, Wright LL. Novel, potent P2-P3 pyrrolidine derivatives of ketoamide-based cathepsin K inhibitors. Bioorg Med Chem Lett. 2006 Mar 15;16(6):1735-9. Epub 2006 Jan 11. PMID:16376075 doi:10.1016/j.bmcl.2005.11.101
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