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2  structures 18  species 1  interaction 63  sequences 2  architectures

Family: Pepsin-I3 (PF06394)

Summary: Pepsin inhibitor-3-like repeated domain

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Pepsin inhibitor-3-like repeated domain Provide feedback

Pepsin inhibitor-3 consisting of two domains, each comprising an antiparallel beta-sheet flanked by an alpha-helix. In the enzyme-inhibitor complex, the N-terminal beta-strand of PI-3 pairs with one strand of the active site flap region of pepsin [1]. The two domains are tandem repeats of sequence, and has therefore been termed repeated domain.

Literature references

  1. Ng KK, Petersen JF, Cherney MM, Garen C, Zalatoris JJ, Rao-Naik C, Dunn BM, Martzen MR, Peanasky RJ, James MN; , Nat Struct Biol 2000;7:653-657.: Structural basis for the inhibition of porcine pepsin by Ascaris pepsin inhibitor-3. PUBMED:10932249 EPMC:10932249


External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR010480

Peptide proteinase inhibitors can be found as single domain proteins or as single or multiple domains within proteins; these are referred to as either simple or compound inhibitors, respectively. In many cases they are synthesised as part of a larger precursor protein, either as a prepropeptide or as an N-terminal domain associated with an inactive peptidase or zymogen. This domain prevents access of the substrate to the active site. Removal of the N-terminal inhibitor domain either by interaction with a second peptidase or by autocatalytic cleavage activates the zymogen. Other inhibitors interact direct with proteinases using a simple noncovalent lock and key mechanism; while yet others use a conformational change-based trapping mechanism that depends on their structural and thermodynamic properties.

The members of this group of proteins belong to MEROPS inhibitor family I33, clan IR; the nematode aspartyl protease inhibitors or Aspins. They are restricted to parasitic nematode species. Structural features common to the nematode Aspins include the presence of a signal peptide sequence and the conservation of all four cysteine residues in the mature protein. The Y[V.A]RDLT sequence motif has been suggested as being of crucial functional importance in several filarial nematode inhibitors [PUBMED:8433724], this sequence is not conserved in Tco-API-1 from Trichostrongylus colubriformis (Black scour worm) and it has been demonstrated that Tco-API-1, is not an Aspin as it does not inhibit porcine pepsin [PUBMED:13678638]. Related inhibitors from Onchocerca volvulus, Ov33 [PUBMED:9392607] and Ascaris suum (Pig roundworm), PI-3 [PUBMED:9654082] inhibit the in vitro activity of aspartyl proteases such as pepsin and cathepsin E (MEROPS peptidase family A1).

Aspin may facilitate the safe passage of the eggs of Ascaris through the host stomach without digestion by pepsin [PUBMED:3916913, PUBMED:9654082]. The other parasitic nematodes known to express homologous proteins do not pass through the stomach of their hosts [PUBMED:10896483]. Several proteins in the family are potent allergens in mammals.

The three-dimensional structures of pepsin inhibitor-3 (PI-3) from A. suum and of the complex between PI-3 and porcine pepsin at 1. 75 A and 2.45 A resolution, respectively, have revealed the mechanism of aspartic protease inhibition. PI-3 has a new fold consisting of two identical domains, each comprising an antiparallel beta-sheet flanked by an alpha-helix. In the enzyme-inhibitor complex, the N-terminal beta-strand of PI-3 pairs with one strand of the 'active site flap' (residues 70-82) of pepsin, thus forming an eight-stranded beta-sheet that spans the two proteins. PI-3 has a novel mode of inhibition, using its N-terminal residues to occupy and therefore block the first three binding pockets in pepsin for substrate residues C-terminal to the scissile bond (S1'-S3') [PUBMED:10932249].

Domain organisation

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

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Alignments

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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.

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(13)
Full
(63)
Representative proteomes NCBI
(64)
Meta
(0)
RP15
(14)
RP35
(18)
RP55
(35)
RP75
(35)
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Format an alignment

  Seed
(13)
Full
(63)
Representative proteomes NCBI
(64)
Meta
(0)
RP15
(14)
RP35
(18)
RP55
(35)
RP75
(35)
Alignment:
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Sequence:
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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
(13)
Full
(63)
Representative proteomes NCBI
(64)
Meta
(0)
RP15
(14)
RP35
(18)
RP55
(35)
RP75
(35)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download    
Gzipped 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.

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: Pfam-B_13438 (release 9.0)
Previous IDs: none
Type: Domain
Author: Finn RD
Number in seed: 13
Number in full: 63
Average length of the domain: 70.30 aa
Average identity of full alignment: 29 %
Average coverage of the sequence by the domain: 53.54 %

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 20.6 20.6
Trusted cut-off 21.0 21.2
Noise cut-off 20.4 20.5
Model length: 76
Family (HMM) version: 8
Download: download the raw HMM for this family

Species distribution

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Interactions

There is 1 interaction for this family. More...

Asp

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 Pepsin-I3 domain has been found. There are 2 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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