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213  structures 273  species 4  interactions 4915  sequences 353  architectures

Family: Kunitz_BPTI (PF00014)

Summary: Kunitz/Bovine pancreatic trypsin inhibitor domain

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Kunitz domain Edit Wikipedia article

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
Symbol Kunitz_BPTI
Pfam PF00014
InterPro IPR002223
PROSITE PDOC00252
SCOP 5pti
SUPERFAMILY 5pti
CDD cd00109

Kunitz domains are the active domains of proteins that inhibit the function of protein degrading enzymes or, more specifically, domains of Kunitz-type 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).

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

Structure[edit]

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[edit]

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[edit]

Human proteins containing this domain include:

References[edit]

  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 Biol. Crystallogr. 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. ^ a b 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. doi:10.1016/0014-5793(94)00941-4. PMID 7925983. 
  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. 
  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. 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. ^ a b 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. 
  12. ^ Dyax Corp. (2009). "Full prescibing information Kalbitor". Retrieved 2010-05-02. 
  13. ^ ClinicalTrials.gov NCT00455767 Safety and Efficacy Study of Depelestat in Acute Respiratory Distress Syndrome (ARDS) Patients
  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. 

This article incorporates text from the public domain Pfam and InterPro IPR002223

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Kunitz/Bovine pancreatic trypsin inhibitor domain Provide feedback

Indicative of a protease inhibitor, usually a serine protease inhibitor. Structure is a disulfide rich alpha+beta fold. BPTI (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 [1]. TAP molecules are highly dipolar [2] and are arranged to form a twisted two- stranded antiparallel beta-sheet followed by an alpha helix [1].

Literature references

  1. Antuch W, Guntert P, Billeter M, Hawthorne T, Grossenbacher H, Wuthrich K; , FEBS Lett 1994;352:251-257.: NMR solution structure of the recombinant tick anticoagulant protein (rTAP), a factor Xa inhibitor from the tick Ornithodoros moubata. PUBMED:7925983 EPMC:7925983

  2. St Charles R, Padmanabhan K, Arni RV, Padmanabhan KP, Tulinsky A; , Protein Sci 2000;9:265-272.: Structure of tick anticoagulant peptide at 1.6 A resolution complexed with bovine pancreatic trypsin inhibitor. PUBMED:10716178 EPMC:10716178


External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR002223

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 [PUBMED:14705960] and are restricted to the metazoa with a single exception: Amsacta moorei entomopoxvirus. They are short (~50 residue) alpha/beta proteins with few secondary structures. The fold is constrained by 3 disulphide bonds. The type example for this family is aprotinin (bovine pancreatic trypsin inhibitor) [PUBMED:1714504] (or basic protease inhibitor), but the family includes numerous other members [PUBMED:1703675, PUBMED:1593645, PUBMED:8159751, PUBMED:1304909], such as snake venom basic protease; mammalian inter-alpha-trypsin inhibitors; trypstatin, a rodent 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 VII and type VI collagens; and tissue factor pathway inhibitor precursor.

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan Protease_inhib (CL0454), which contains the following 2 members:

Kunitz_BPTI WAP

Alignments

We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics sequence database. More...

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We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

  Seed
(147)
Full
(4915)
Representative proteomes NCBI
(4772)
Meta
(22)
RP15
(878)
RP35
(1112)
RP55
(2046)
RP75
(2635)
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Format an alignment

  Seed
(147)
Full
(4915)
Representative proteomes NCBI
(4772)
Meta
(22)
RP15
(878)
RP35
(1112)
RP55
(2046)
RP75
(2635)
Alignment:
Format:
Order:
Sequence:
Gaps:
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We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

  Seed
(147)
Full
(4915)
Representative proteomes NCBI
(4772)
Meta
(22)
RP15
(878)
RP35
(1112)
RP55
(2046)
RP75
(2635)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download  
Gzipped Download   Download   Download   Download   Download   Download   Download   Download  

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

Pfam alignments:

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Prosite
Previous IDs: none
Type: Domain
Author: Fenech M
Number in seed: 147
Number in full: 4915
Average length of the domain: 53.40 aa
Average identity of full alignment: 35 %
Average coverage of the sequence by the domain: 18.48 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 21.0 21.0
Trusted cut-off 21.0 21.0
Noise cut-off 20.9 20.9
Model length: 53
Family (HMM) version: 18
Download: download the raw HMM for this family

Species distribution

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Interactions

There are 4 interactions for this family. More...

Phospholip_A2_1 Trypsin Kunitz_BPTI Peptidase_S7

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Kunitz_BPTI domain has been found. There are 213 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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