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 . The two domains are tandem repeats of sequence, and has therefore been termed repeated domain.
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
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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].
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Curation and family details
|Seed source:||Pfam-B_13438 (release 9.0)|
|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 build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||8|
|Download:||download the raw HMM for this family|
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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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