| Kunitz/Bovine pancreatic trypsin inhibitor domain | |||||||||||
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| Identifiers | |||||||||||
| Symbol | Kunitz_BPTI | ||||||||||
| Pfam | PF00014 | ||||||||||
| InterPro | IPR002223 | ||||||||||
| PROSITE | PDOC00252 | ||||||||||
| SCOP2 | 5pti /SCOPe /SUPFAM | ||||||||||
| CDD | cd00109 | ||||||||||
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Kunitz domains are the activedomains ofproteins that inhibit the function ofprotein degrading enzymes or, more specifically, domains of Kunitz-type areprotease inhibitors. They are relatively small with a length of about 50 to 60amino acids and a molecular weight of 6kDa. Examples of Kunitz-type protease inhibitors areaprotinin (bovine pancreatic trypsin inhibitor, BPTI), Alzheimer'samyloid precursor protein (APP), andtissue factor pathway inhibitor (TFPI).Kunitz STI protease inhibitor, the trypsin inhibitor initially studied byMoses Kunitz, was extracted fromsoybeans.
Standalone Kunitz domains are used as a framework for the development of newpharmaceutical drugs.[2]
The structure is adisulfide rich alpha+beta fold. Bovine pancreatic trypsin inhibitor is an extensively studied model structure. Certain family members are similar to thetick anticoagulant peptide (TAP,P17726). This is a highly selective inhibitor offactor Xa in the blood coagulation pathways.[3] TAP molecules are highlydipolar,[4] and are arranged to form a twisted two-stranded antiparallelbeta sheet followed by analpha helix.[3]
The majority of the sequences having this domain belong to theMEROPS inhibitor family I2, clan IB; the Kunitz/bovine pancreatic trypsin inhibitor family, they inhibit proteases of the S1 family[5] and are restricted to themetazoa with a single exception:Amsacta moorei entomopoxvirus, a species ofpoxvirus. 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; mammalianinter-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 theC-termini of thealpha-1 andalpha-3 chains of type VI and type VIIcollagens; tissue factor pathway inhibitor precursor; andKunitz STI protease inhibitor contained inlegume seeds.
Kunitz domains are stable as standalonepeptides, able to recognise specific protein structures, and also work ascompetitive protease inhibitors in their free form. These properties have led to attempts at developingbiopharmaceutical drugs from Kunitz domains. Candidate domains are selected from molecular libraries containing over 10 million variants with the aid of display techniques likephage display,[11] and can be produced in large scale bygenetically engineered organisms.
The first of these drugs to be marketed was thekallikrein inhibitorecallantide, used for the treatment of hereditaryangioedema.[11] It was approved in the United States in 2009.[12] Another example isdepelestat, an inhibitor ofneutrophil elastase that has undergone Phase IIclinical trials for the treatment ofacute respiratory distress syndrome in 2006/2007[13] and has also been described as a potential inhalablecystic fibrosis treatment.[14]
Human proteins containing this domain include:
Several plant protease inhibitors of the Kunitz family, theKunitz-STI protein family, include abeta trefoil fold.[15]
Engineeredmonoclonal antibodies andantibody mimetics | ||
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| Whole antibody |  | |
| Fab fragment | ||
| Variable fragment | ||
| Smaller units | ||
| Intracellular | ||
| Antibody mimetics | ||