4cdc: Difference between revisions

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==Human DPP1 in complex with (2S)-2-amino-N-((1S)-1-cyano-2-(4- phenylphenyl)ethyl)butanamide==
==Human DPP1 in complex with (2S)-2-amino-N-((1S)-1-cyano-2-(4- phenylphenyl)ethyl)butanamide==
<StructureSection load='4cdc' size='340' side='right' caption='[[4cdc]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
<StructureSection load='4cdc' size='340' side='right'caption='[[4cdc]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4cdc]] is a 12 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=4CDC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4CDC FirstGlance]. <br>
<table><tr><td colspan='2'>[[4cdc]] is a 12 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=4CDC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4CDC FirstGlance]. <br>
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==See Also==
==See Also==
*[[Cathepsin|Cathepsin]]
*[[Dipeptidyl peptidase|Dipeptidyl peptidase]]
*[[Dipeptidyl peptidase|Dipeptidyl peptidase]]
== References ==
== References ==
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[[Category: Dipeptidyl-peptidase I]]
[[Category: Dipeptidyl-peptidase I]]
[[Category: Human]]
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Breed, J]]
[[Category: Breed, J]]
[[Category: Cage, P]]
[[Category: Cage, P]]

Revision as of 11:53, 20 March 2019

Human DPP1 in complex with (2S)-2-amino-N-((1S)-1-cyano-2-(4- phenylphenyl)ethyl)butanamideHuman DPP1 in complex with (2S)-2-amino-N-((1S)-1-cyano-2-(4- phenylphenyl)ethyl)butanamide

Structural highlights

4cdc is a 12 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:, , ,
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

A lead generation and optimization program delivered the highly selective and potent CatC inhibitor 10 as an in vivo tool compound and potential development candidate. Structural studies were undertaken to generate SAR understanding.

Cathepsin C Inhibitors: Property Optimization and Identification of a Clinical Candidate.,Furber M, Tiden AK, Gardiner P, Mete A, Ford R, Millichip I, Stein L, Mather A, Kinchin E, Luckhurst C, Barber S, Cage P, Sanganee H, Austin R, Chohan K, Beri R, Thong B, Wallace A, Oreffo V, Hutchinson R, Harper S, Debreczeni J, Breed J, Wissler L, Edman K J Med Chem. 2014 Mar 14. PMID:24592859[17]

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

See Also

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. ↑ Furber M, Tiden AK, Gardiner P, Mete A, Ford R, Millichip I, Stein L, Mather A, Kinchin E, Luckhurst C, Barber S, Cage P, Sanganee H, Austin R, Chohan K, Beri R, Thong B, Wallace A, Oreffo V, Hutchinson R, Harper S, Debreczeni J, Breed J, Wissler L, Edman K. Cathepsin C Inhibitors: Property Optimization and Identification of a Clinical Candidate. J Med Chem. 2014 Mar 14. PMID:24592859 doi:http://dx.doi.org/10.1021/jm401705g

4cdc, resolution 2.40Å

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