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'''Unreleased structure'''


The entry 6ic7 is ON HOLD
==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.


Authors: Hakansson, M., Logan, D.T., Korkmaz, B., Lesner, A., Wysoxka, M., Gieldon, A., Gauthier, F., Jenne, D., Lauritzen, C., Pedersen, J.
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>


Description: Human cathepsin-C in complex with cyclopropyl peptidyl nitrile inhibitor 3
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[Category: Unreleased Structures]]
</div>
[[Category: Logan, D.T]]
<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: Gauthier, F]]
[[Category: Lauritzen, C]]
[[Category: Gieldon, A]]
[[Category: Wysoxka, M]]
[[Category: Hakansson, M]]
[[Category: Hakansson, M]]
[[Category: Pedersen, J]]
[[Category: Jenne, D]]
[[Category: Korkmaz, B]]
[[Category: Korkmaz, B]]
[[Category: Jenne, D]]
[[Category: Lauritzen, C]]
[[Category: Gieldon, A]]
[[Category: Lesner, A]]
[[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]]

Latest revision as of 10:33, 23 May 2019

Human cathepsin-C in complex with dipeptidyl cyclopropyl nitrile inhibitor 3Human cathepsin-C in complex with dipeptidyl cyclopropyl nitrile inhibitor 3

Structural highlights

6ic7 is a 3 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:, , , ,
Gene:CTSC, CPPI (HUMAN)
Activity:Dipeptidyl-peptidase I, with EC number 3.4.14.1
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[CATC_HUMAN] Defects in CTSC are a cause of Papillon-Lefevre syndrome (PLS) [MIM: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.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] Defects in CTSC are a cause of Haim-Munk syndrome (HMS) [MIM: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.[13] Defects in CTSC are a cause of aggressive periodontititis type 1 (AP1) [MIM: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.[14] [15]

Function

[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.[16]

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[17]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Allende LM, Garcia-Perez MA, Moreno A, Corell A, Carasol M, Martinez-Canut P, Arnaiz-Villena A. Cathepsin C gene: First compound heterozygous patient with Papillon-Lefevre syndrome and a novel symptomless mutation. Hum Mutat. 2001 Feb;17(2):152-3. PMID:11180601 doi:<152::AID-HUMU10>3.0.CO;2-# 10.1002/1098-1004(200102)17:2<152::AID-HUMU10>3.0.CO;2-#
  2. ↑ Allende LM, Moreno A, de Unamuno P. A genetic study of cathepsin C gene in two families with Papillon-Lefevre syndrome. Mol Genet Metab. 2003 Jun;79(2):146-8. PMID:12809647
  3. ↑ Toomes C, James J, Wood AJ, Wu CL, McCormick D, Lench N, Hewitt C, Moynihan L, Roberts E, Woods CG, Markham A, Wong M, Widmer R, Ghaffar KA, Pemberton M, Hussein IR, Temtamy SA, Davies R, Read AP, Sloan P, Dixon MJ, Thakker NS. Loss-of-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis. Nat Genet. 1999 Dec;23(4):421-4. PMID:10581027 doi:10.1038/70525
  4. ↑ Hart TC, Hart PS, Michalec MD, Zhang Y, Marazita ML, Cooper M, Yassin OM, Nusier M, Walker S. Localisation of a gene for prepubertal periodontitis to chromosome 11q14 and identification of a cathepsin C gene mutation. J Med Genet. 2000 Feb;37(2):95-101. PMID:10662808
  5. ↑ Hart PS, Zhang Y, Firatli E, Uygur C, Lotfazar M, Michalec MD, Marks JJ, Lu X, Coates BJ, Seow WK, Marshall R, Williams D, Reed JB, Wright JT, Hart TC. Identification of cathepsin C mutations in ethnically diverse papillon-Lefevre syndrome patients. J Med Genet. 2000 Dec;37(12):927-32. PMID:11106356
  6. ↑ Nakano A, Nomura K, Nakano H, Ono Y, LaForgia S, Pulkkinen L, Hashimoto I, Uitto J. Papillon-Lefevre syndrome: mutations and polymorphisms in the cathepsin C gene. J Invest Dermatol. 2001 Feb;116(2):339-43. PMID:11180012 doi:10.1046/j.1523-1747.2001.01244.x
  7. ↑ Lefevre C, Blanchet-Bardon C, Jobard F, Bouadjar B, Stalder JF, Cure S, Hoffmann A, Prud'Homme JF, Fischer J. Novel point mutations, deletions, and polymorphisms in the cathepsin C gene in nine families from Europe and North Africa with Papillon-Lefevre syndrome. J Invest Dermatol. 2001 Dec;117(6):1657-61. PMID:11886537 doi:1595
  8. ↑ Zhang Y, Lundgren T, Renvert S, Tatakis DN, Firatli E, Uygur C, Hart PS, Gorry MC, Marks JJ, Hart TC. Evidence of a founder effect for four cathepsin C gene mutations in Papillon-Lefevre syndrome patients. J Med Genet. 2001 Feb;38(2):96-101. PMID:11158173
  9. ↑ Zhang Y, Hart PS, Moretti AJ, Bouwsma OJ, Fisher EM, Dudlicek L, Pettenati MJ, Hart TC. Biochemical and mutational analyses of the cathepsin c gene (CTSC) in three North American families with Papillon Lefevre syndrome. Hum Mutat. 2002 Jul;20(1):75. PMID:12112662 doi:10.1002/humu.9040
  10. ↑ Hewitt C, McCormick D, Linden G, Turk D, Stern I, Wallace I, Southern L, Zhang L, Howard R, Bullon P, Wong M, Widmer R, Gaffar KA, Awawdeh L, Briggs J, Yaghmai R, Jabs EW, Hoeger P, Bleck O, Rudiger SG, Petersilka G, Battino M, Brett P, Hattab F, Al-Hamed M, Sloan P, Toomes C, Dixon M, James J, Read AP, Thakker N. The role of cathepsin C in Papillon-Lefevre syndrome, prepubertal periodontitis, and aggressive periodontitis. Hum Mutat. 2004 Mar;23(3):222-8. PMID:14974080 doi:10.1002/humu.10314
  11. ↑ de Haar SF, Jansen DC, Schoenmaker T, De Vree H, Everts V, Beertsen W. Loss-of-function mutations in cathepsin C in two families with Papillon-Lefevre syndrome are associated with deficiency of serine proteinases in PMNs. Hum Mutat. 2004 May;23(5):524. PMID:15108292 doi:10.1002/humu.9243
  12. ↑ de Haar SF, Mir M, Nguyen M, Kazemi B, Ramezani GH, Everts V, Beertsen W. Gene symbol: CTSC. Disease: Papillon-Lefevre syndrome. Hum Genet. 2005 May;116(6):545. PMID:15991336
  13. ↑ Hart TC, Hart PS, Michalec MD, Zhang Y, Firatli E, Van Dyke TE, Stabholz A, Zlotogorski A, Shapira L, Soskolne WA. Haim-Munk syndrome and Papillon-Lefevre syndrome are allelic mutations in cathepsin C. J Med Genet. 2000 Feb;37(2):88-94. PMID:10662807
  14. ↑ Hart TC, Hart PS, Michalec MD, Zhang Y, Marazita ML, Cooper M, Yassin OM, Nusier M, Walker S. Localisation of a gene for prepubertal periodontitis to chromosome 11q14 and identification of a cathepsin C gene mutation. J Med Genet. 2000 Feb;37(2):95-101. PMID:10662808
  15. ↑ Hewitt C, McCormick D, Linden G, Turk D, Stern I, Wallace I, Southern L, Zhang L, Howard R, Bullon P, Wong M, Widmer R, Gaffar KA, Awawdeh L, Briggs J, Yaghmai R, Jabs EW, Hoeger P, Bleck O, Rudiger SG, Petersilka G, Battino M, Brett P, Hattab F, Al-Hamed M, Sloan P, Toomes C, Dixon M, James J, Read AP, Thakker N. The role of cathepsin C in Papillon-Lefevre syndrome, prepubertal periodontitis, and aggressive periodontitis. Hum Mutat. 2004 Mar;23(3):222-8. PMID:14974080 doi:10.1002/humu.10314
  16. ↑ McGuire MJ, Lipsky PE, Thiele DL. Purification and characterization of dipeptidyl peptidase I from human spleen. Arch Biochem Biophys. 1992 Jun;295(2):280-8. PMID:1586157
  17. ↑ Korkmaz B, Lesner A, Wysocka M, Gieldon A, Hakansson M, Gauthier F, Logan DT, Jenne D, Lauritzen C, Pedersen J. Structure-based design and in vivo anti-arthritic activity evaluation of a potent dipeptidyl cyclopropyl nitrile inhibitor of cathepsin C. Biochem Pharmacol. 2019 Apr 9. pii: S0006-2952(19)30141-8. doi:, 10.1016/j.bcp.2019.04.006. PMID:30978322 doi:http://dx.doi.org/10.1016/j.bcp.2019.04.006

6ic7, resolution 2.00Å

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