Kunitz domain

Last updated
Kunitz/Bovine pancreatic trypsin inhibitor domain
PDB 1kth EBI.jpg
3D structure of the C-terminal Kunitz domain from human collagen alpha-3(VI) chain. [1]
Identifiers
SymbolKunitz_BPTI
Pfam PF00014
InterPro IPR002223
PROSITE PDOC00252
SCOP2 5pti / SCOPe / SUPFAM
CDD cd00109
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
PDB 1knt :3110-3162 2knt :3110-3162 1kth A:3110-3162

1kun :3110-3162 1bik :286-338 1shp :2-54 1jc6 A:6-58 1bf0 :6-58 1dtk :26-78 1dtx :6-58 1den :6-58 1dem :6-58 1zr0 D:35-87 1irh A:216-268 1adz :124-176 1tfx C:124-176 1d0d B:39-91 1k6u A:39-91 2fi4 I:39-91 1aal A:39-91 2kai I:39-91 1ejm D:39-91 1fak I:39-90 1bhc G:39-91 2hex C:39-91 1bth Q:39-91 3btw I:39-91 1p2q B:39-91 1bz5 C:39-91 3bth I:39-91 1oa6 5:39-91 1eaw B:39-91 3btm I:39-91 1oa5 5:39-91 2tpi I:39-91 1pit :39-91 3btd I:39-91 1b0c D:39-91 3btf I:39-91 1t8m B:39-91 1ld5 A:39-91 1bzx I:39-91 1p2j I:39-91 1uub A:39-91 3tgk I:39-91 1t7c D:39-91 1tpa I:39-91 1p2n B:39-91 1p2k I:39-91 1t8n B:39-91 1g6x A:39-91 1nag :39-91 8pti :39-91 2fi3 I:39-91 1t8o B:39-91 1k09 B:50-73 1p2m B:39-91 6pti :39-91 3tpi I:39-91 1t8l D:39-91 3btg I:39-91 3tgj I:39-91 1brb I:42-90 1jv9 A:39-91 1f7z I:39-91 1fy8 I:39-91 2ptc I:39-91 2tgp I:39-91 1mtn D:39-91 1cbw I:39-91 1jv8 A:39-91 1f5r I:39-91 7pti :39-91 3bte I:39-91 1fan :39-91 3tgi I:39-91 3btk I:39-91 5pti :39-91 1uua A:39-91 9pti :39-91 3btt I:39-91 1bpi :39-91 1p2o D:39-91 1bpt :39-91 1p2i I:39-91 4pti :39-91 1qlq A:39-91 1ld6 A:39-91 3btq I:39-91 4tpi I:39-91 1bti :39-91 1yc0 I:249-301 1ca0 I:290-342 1aap B:290-342 1taw B:290-342 1brc I:290-342 1zjd B:290-342 1bun B:30-82 1toc R:4-51

Contents

1kig I:4-60 1tap :4-60 1tcp :4-60

Kunitz domains are the active domains of proteins that inhibit the function of protein degrading enzymes or, more specifically, domains of Kunitz-type are protease inhibitors. They are relatively small with a length of about 50 to 60 amino acids and a molecular weight of 6 kDa. Examples of Kunitz-type protease inhibitors are aprotinin (bovine pancreatic trypsin inhibitor, BPTI), Alzheimer's amyloid precursor protein (APP), and tissue factor pathway inhibitor (TFPI). Kunitz STI protease inhibitor, the trypsin inhibitor initially studied by Moses Kunitz, was extracted from soybeans.

Standalone Kunitz domains are used as a framework for the development of new pharmaceutical drugs. [2]

Structure

The structure is a disulfide rich alpha+beta fold. Bovine pancreatic trypsin inhibitor is an extensively studied model structure. Certain family members are similar to the tick anticoagulant peptide (TAP, P17726 ). This is a highly selective inhibitor of factor Xa in the blood coagulation pathways. [3] TAP molecules are highly dipolar, [4] and are arranged to form a twisted two-stranded antiparallel beta sheet followed by an alpha helix. [3]

The majority of the sequences having this domain belong to the MEROPS inhibitor family I2, clan IB; the Kunitz/bovine pancreatic trypsin inhibitor family, they inhibit proteases of the S1 family [5] and are restricted to the metazoa with a single exception: Amsacta moorei entomopoxvirus, a species of poxvirus. They are short (about 50 to 60 amino acid residues) alpha/beta proteins with few secondary structures. The fold is constrained by three disulfide bonds. The type example for this family is BPTI [6] (or basic protease inhibitor), but the family includes numerous other members, [7] [8] [9] [10] such as snake venom basic protease; mammalian inter-alpha-trypsin inhibitors; trypstatin, a rat mast cell inhibitor of trypsin; a domain found in an alternatively spliced form of Alzheimer's amyloid beta-protein; domains at the C-termini of the alpha-1 and alpha-3 chains of type VI and type VII collagens; tissue factor pathway inhibitor precursor; and Kunitz STI protease inhibitor contained in legume seeds.

Drug development

Kunitz domains are stable as standalone peptides, able to recognise specific protein structures, and also work as competitive protease inhibitors in their free form. These properties have led to attempts at developing biopharmaceutical drugs from Kunitz domains. Candidate domains are selected from molecular libraries containing over 10 million variants with the aid of display techniques like phage display, [11] and can be produced in large scale by genetically engineered organisms.

The first of these drugs to be marketed was the kallikrein inhibitor ecallantide, used for the treatment of hereditary angioedema. [11] It was approved in the United States in 2009. [12] Another example is depelestat, an inhibitor of neutrophil elastase that has undergone Phase II clinical trials for the treatment of acute respiratory distress syndrome in 2006/2007 [13] and has also been described as a potential inhalable cystic fibrosis treatment. [14]

Examples

Human proteins containing this domain include:

Several plant protease inhibitors of the Kunitz family, the Kunitz-STI protein family, include a beta trefoil fold. [15]

References

  1. ↑ PDB: 1KTH ​; Arnoux B, Ducruix A, Prangé T (July 2002). "Anisotropic behaviour of the C-terminal Kunitz-type domain of the alpha3 chain of human type VI collagen at atomic resolution (0.9 Å)". Acta Crystallogr. D. 58 (Pt 7): 1252–4. doi:10.1107/S0907444902007333. PMID   12077460.
  2. ↑ Nixon, AE; Wood, CR (2006). "Engineered protein inhibitors of proteases". Current Opinion in Drug Discovery & Development. 9 (2): 261–8. PMID   16566296.
  3. 1 2 Antuch W, Güntert P, Billeter M, Hawthorne T, Grossenbacher H, Wüthrich K (September 1994). "NMR solution structure of the recombinant tick anticoagulant protein (rTAP), a factor Xa inhibitor from the tick Ornithodoros moubata". FEBS Lett. 352 (2): 251–7. Bibcode:1994FEBSL.352..251A. doi: 10.1016/0014-5793(94)00941-4 . PMID   7925983. S2CID   2280234.
  4. ↑ St Charles R, Padmanabhan K, Arni RV, Padmanabhan KP, Tulinsky A (February 2000). "Structure of tick anticoagulant peptide at 1.6 A resolution complexed with bovine pancreatic trypsin inhibitor". Protein Sci. 9 (2): 265–72. doi:10.1110/ps.9.2.265. PMC   2144540 . PMID   10716178.
  5. ↑ Rawlings ND, Barrett AJ, Tolle DP (2004). "Evolutionary families of peptidase inhibitors". Biochem. J. 378 (Pt 3): 705–16. doi:10.1042/BJ20031825. PMC   1224039 . PMID   14705960.
  6. ↑ Wlodawer A, Housset D, Kim KS, Fuchs J, Woodward C (1991). "Crystal structure of a Y35G mutant of bovine pancreatic trypsin inhibitor". J. Mol. Biol. 220 (3): 757–770. doi:10.1016/0022-2836(91)90115-M. PMID   1714504.
  7. ↑ Salier JP (1990). "Inter-alpha-trypsin inhibitor: emergence of a family within the Kunitz-type protease inhibitor superfamily". Trends Biochem. Sci. 15 (11): 435–439. doi:10.1016/0968-0004(90)90282-G. PMID   1703675.
  8. ↑ Takahashi K, Ikeo K, Gojobori T (1992). "Evolutionary origin of a Kunitz-type trypsin inhibitor domain inserted in the amyloid beta precursor protein of Alzheimer's disease". J. Mol. Evol. 34 (6): 536–543. doi:10.1007/BF00160466. PMID   1593645. S2CID   26698630.
  9. ↑ Sprecher CA, Foster DC, Kisiel W, Mathewes S (1994). "Molecular cloning, expression, and partial characterization of a second human tissue-factor-pathway inhibitor". Proc. Natl. Acad. Sci. U.S.A. 91 (8): 3353–3357. Bibcode:1994PNAS...91.3353S. doi: 10.1073/pnas.91.8.3353 . PMC   43575 . PMID   8159751.
  10. ↑ Biemann K, Papayannopoulos IA (1992). "Amino acid sequence of a protease inhibitor isolated from Sarcophaga bullata determined by mass spectrometry". Protein Sci. 1 (2): 278–288. doi:10.1002/pro.5560010210. PMC   2142190 . PMID   1304909.
  11. 1 2 Lehmann, A (2008). "Ecallantide (DX-88), a plasma kallikrein inhibitor for the treatment of hereditary angioedema and the prevention of blood loss in on-pump cardiothoracic surgery". Expert Opinion on Biological Therapy. 8 (8): 1187–99. doi:10.1517/14712598.8.8.1187. PMID   18613770. S2CID   72623604.
  12. ↑ Dyax Corp. (2009). "Full prescibing information Kalbitor" (PDF). Retrieved 2010-05-02.
  13. ↑ Clinical trial number NCT00455767 for "Safety and Efficacy Study of Depelestat in Acute Respiratory Distress Syndrome (ARDS) Patients" at ClinicalTrials.gov
  14. ↑ Attucci, S; Gauthier, A; Korkmaz, B; Delépine, P; Martino, MF; Saudubray, F; Diot, P; Gauthier, F (2006). "EPI-hNE4, a proteolysis-resistant inhibitor of human neutrophil elastase and potential anti-inflammatory drug for treating cystic fibrosis". The Journal of Pharmacology and Experimental Therapeutics. 318 (2): 803–9. doi:10.1124/jpet.106.103440. PMID   16627747. S2CID   1771342.
  15. ↑ Azarkan M, Martinez-Rodriguez S, Buts L, Baeyens-Volant D, Garcia-Pino A (Dec 2011). "The plasticity of the β-trefoil fold constitutes an evolutionary platform for protease inhibition". The Journal of Biological Chemistry. 286 (51): 43726–34. doi: 10.1074/jbc.M111.291310 . PMC   3243510 . PMID   22027836.
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