View source for 2ftd


==Crystal structure of Cathepsin K complexed with 7-Methyl-Substituted Azepan-3-one compound==
<StructureSection load='2ftd' size='340' side='right'caption='[[2ftd]], [[Resolution|resolution]] 2.55&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2ftd]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Macmu Macmu]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2FTD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2FTD FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ILI:N-[(1S)-1-({[(3S,4S,7R)-3-HYDROXY-7-METHYL-1-(PYRIDIN-2-YLSULFONYL)-2,3,4,7-TETRAHYDRO-1H-AZEPIN-4-YL]AMINO}CARBONYL)-3-METHYLBUTYL]-1-BENZOFURAN-2-CARBOXAMIDE'>ILI</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1au0|1au0]], [[1au2|1au2]], [[1au3|1au3]], [[1au4|1au4]]</div></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CTSK ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9544 MACMU])</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=2ftd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ftd OCA], [https://pdbe.org/2ftd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2ftd RCSB], [https://www.ebi.ac.uk/pdbsum/2ftd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2ftd ProSAT]</span></td></tr>
</table>
== Function ==
[[https://www.uniprot.org/uniprot/CATK_MACMU CATK_MACMU]] 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). 
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ft/2ftd_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2ftd ConSurf].
<div style="clear:both"></div>
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== Publication Abstract from PubMed ==
The syntheses, in vitro characterizations, and rat and monkey in vivo pharmacokinetic profiles of a series of 5-, 6-, and 7-methyl-substituted azepanone-based cathepsin K inhibitors are described. Depending on the particular regiochemical substitution and stereochemical configuration, methyl-substituted azepanones were identified that had widely varied cathepsin K inhibitory potency as well as pharmacokinetic properties compared to the 4S-parent azepanone analogue, 1 (human cathepsin K, K(i,app) = 0.16 nM, rat oral bioavailability = 42%, rat in vivo clearance = 49.2 mL/min/kg). Of particular note, the 4S-7-cis-methylazepanone analogue, 10, had a K(i,app) = 0.041 nM vs human cathepsin K and 89% oral bioavailability and an in vivo clearance rate of 19.5 mL/min/kg in the rat. Hypotheses that rationalize some of the observed characteristics of these closely related analogues have been made using X-ray crystallography and conformational analysis. These examples demonstrate the potential for modulation of pharmacological properties of cathepsin inhibitors by substituting the azepanone core. The high potency for inhibition of cathepsin K coupled with the favorable rat and monkey pharmacokinetic characteristics of compound 10, also known as SB-462795 or relacatib, has made it the subject of considerable in vivo evaluation for safety and efficacy as an inhibitor of excessive bone resorption in rat, monkey, and human studies, which will be reported elsewhere.

Structure activity relationships of 5-, 6-, and 7-methyl-substituted azepan-3-one cathepsin K inhibitors.,Yamashita DS, Marquis RW, Xie R, Nidamarthy SD, Oh HJ, Jeong JU, Erhard KF, Ward KW, Roethke TJ, Smith BR, Cheng HY, Geng X, Lin F, Offen PH, Wang B, Nevins N, Head MS, Haltiwanger RC, Narducci Sarjeant AA, Liable-Sands LM, Zhao B, Smith WW, Janson CA, Gao E, Tomaszek T, McQueney M, James IE, Gress CJ, Zembryki DL, Lark MW, Veber DF J Med Chem. 2006 Mar 9;49(5):1597-612. PMID:16509577<ref>PMID:16509577</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 2ftd" style="background-color:#fffaf0;"></div>

==See Also==
*[[Cathepsin 3D structures|Cathepsin 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Cathepsin K]]
[[Category: Large Structures]]
[[Category: Macmu]]
[[Category: Baoguang, Z]]
[[Category: Yamashita, D S]]
[[Category: Hydrolase]]
[[Category: Sulfhydryl proteinase]]