View source for 6ic7


==Human cathepsin-C in complex with dipeptidyl cyclopropyl nitrile inhibitor 3==
<StructureSection load='6ic7' size='340' side='right'caption='[[6ic7]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6ic7]] is a 3 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=6IC7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6IC7 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=H9H:1-azanyl-~{N}-[(1~{R},2~{R})-1-cyano-2-[4-[4-(4-methylpiperazin-1-yl)sulfonylphenyl]phenyl]cyclopropyl]cyclohexane-1-carboxamide'>H9H</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6ic5|6ic5]], [[6ic6|6ic6]]</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CTSC, CPPI ([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/Dipeptidyl-peptidase_I Dipeptidyl-peptidase I], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.14.1 3.4.14.1] </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=6ic7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ic7 OCA], [http://pdbe.org/6ic7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ic7 RCSB], [http://www.ebi.ac.uk/pdbsum/6ic7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ic7 ProSAT]</span></td></tr>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/CATC_HUMAN CATC_HUMAN]] Defects in CTSC are a cause of Papillon-Lefevre syndrome (PLS) [MIM:[http://omim.org/entry/245000 245000]]; also known as keratosis palmoplantaris with periodontopathia. PLS is an autosomal recessive disorder characterized by palmoplantar keratosis and severe periodontitis affecting deciduous and permanent dentitions and resulting in premature tooth loss. The palmoplantar keratotic phenotype vary from mild psoriasiform scaly skin to overt hyperkeratosis. Keratosis also affects other sites such as elbows and knees.<ref>PMID:11180601</ref> <ref>PMID:12809647</ref> <ref>PMID:10581027</ref> <ref>PMID:10662808</ref> <ref>PMID:11106356</ref> <ref>PMID:11180012</ref> <ref>PMID:11886537</ref> <ref>PMID:11158173</ref> <ref>PMID:12112662</ref> <ref>PMID:14974080</ref> <ref>PMID:15108292</ref> <ref>PMID:15991336</ref>   Defects in CTSC are a cause of Haim-Munk syndrome (HMS) [MIM:[http://omim.org/entry/245010 245010]]; also known as keratosis palmoplantaris with periodontopathia and onychogryposis or Cochin Jewish disorder. HMS is an autosomal recessive disorder characterized by palmoplantar keratosis, onychogryphosis and periodontitis. Additional features are pes planus, arachnodactyly, and acroosteolysis.<ref>PMID:10662807</ref>   Defects in CTSC are a cause of aggressive periodontititis type 1 (AP1) [MIM:[http://omim.org/entry/170650 170650]]; also known as juvenile periodontitis (JPD) and prepubertal periodontitis (PPP). AP1 is characterized by severe and protracted gingival infections, leading to tooth loss. AP1 inheritance is autosomal dominant.<ref>PMID:10662808</ref> <ref>PMID:14974080</ref>  
== Function ==
[[http://www.uniprot.org/uniprot/CATC_HUMAN CATC_HUMAN]] Thiol protease. Has dipeptidylpeptidase activity. Active against a broad range of dipeptide substrates composed of both polar and hydrophobic amino acids. Proline cannot occupy the P1 position and arginine cannot occupy the P2 position of the substrate. Can act as both an exopeptidase and endopeptidase. Activates serine proteases such as elastase, cathepsin G and granzymes A and B. Can also activate neuraminidase and factor XIII.<ref>PMID:1586157</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Cathepsin C (CatC) is a dipeptidyl-exopeptidase which activates neutrophil serine protease precursors (elastase, proteinase 3, cathepsin G and NSP4) by removing their N-terminal propeptide in bone marrow cells at the promyelocytic stage of neutrophil differentiation. The resulting active proteases are implicated in chronic inflammatory and autoimmune diseases. Hence, inhibition of CatC represents a therapeutic strategy to suppress excessive protease activities in various neutrophil mediated diseases. We designed and synthesized a series of dipeptidyl cyclopropyl nitrile compounds as putative CatC inhibitors. One compound, IcatCXPZ-01 ((S)-2-amino-N-((1R,2R)-1-cyano-2-(4'-(4-methylpiperazin-1-ylsulfonyl)biphenyl-4- yl)cyclopropyl)butanamide)) was identified as a potent inhibitor of both human and rodent CatC. In mice, pharmacokinetic studies revealed that IcatCXPZ-01 accumulated in the bone marrow reaching levels suitable for CatC inhibition. Subcutaneous administration of IcatCXPZ-01 in a monoclonal anti-collagen antibody induced mouse model of rheumatoid arthritis resulted in statistically significant anti-arthritic activity with persistent decrease in arthritis scores and paw thickness.

Structure-based design and in vivo anti-arthritic activity evaluation of a potent dipeptidyl cyclopropyl nitrile inhibitor of cathepsin C.,Korkmaz B, Lesner A, Wysocka M, Gieldon A, Hakansson M, Gauthier F, Logan DT, Jenne D, Lauritzen C, Pedersen J Biochem Pharmacol. 2019 Apr 9. pii: S0006-2952(19)30141-8. doi:, 10.1016/j.bcp.2019.04.006. PMID:30978322<ref>PMID:30978322</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6ic7" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Dipeptidyl-peptidase I]]
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Gauthier, F]]
[[Category: Gieldon, A]]
[[Category: Hakansson, M]]
[[Category: Jenne, D]]
[[Category: Korkmaz, B]]
[[Category: Lauritzen, C]]
[[Category: Lesner, A]]
[[Category: Logan, D T]]
[[Category: Pedersen, J]]
[[Category: Wysocka, M]]
[[Category: Arthritis]]
[[Category: Cathepsin-c]]
[[Category: Cysteine protease]]
[[Category: Hydrolase]]
[[Category: Structure-based drug design]]