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3  structures 7  species 1  interaction 7  sequences 1  architecture

Family: Inhibitor_I34 (PF10466)

Summary: Saccharopepsin inhibitor I34

Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.

This is the Wikipedia entry entitled "Protease inhibitor (biology)". More...

Protease inhibitor (biology) Edit Wikipedia article

In biology and biochemistry, protease inhibitors are molecules that inhibit the function of proteases. Many naturally occurring protease inhibitors are proteins.

In medicine, protease inhibitor is often used interchangeably with alpha 1-antitrypsin (A1AT, which is abbreviated PI for this reason).[1] A1AT is indeed the protease inhibitor most often involved in disease, namely in alpha 1-antitrypsin deficiency.

Classification[edit]

Protease inhibitors may be classified either by the type of protease they inhibit, or by their mechanism of action. In 2004 Rawlings and colleagues introduced a classification of protease inhibitors based on similarities detectable at the level of amino acid sequence.[2] This classification initially identified 48 families of inhibitors that could be grouped into 26 related superfamily (or clans) by their structure. According to the MEROPS database there are now 85 families of inhibitors. These families are named with an I followed by a number, for example, I14 contains hirudin-like inhibitors.

By protease[edit]

Classes of proteases are:

By mechanism[edit]

Classes of inhibitor mechanisms of action are:

Families[edit]

Inhibitor I9[edit]

Peptidase inhibitor I9
PDB 1spb EBI.jpg
subtilisin bpn' prosegment (77 residues) complexed with a mutant subtilisin bpn' (266 residues). crystal ph 4.6. crystallization temperature 20 c diffraction temperature-160 c
Identifiers
Symbol Inhibitor_I9
Pfam PF05922
InterPro IPR010259
MEROPS I9
SCOP 1gns
SUPERFAMILY 1gns

Proteinase propeptide inhibitors (sometimes referred to as activation peptides) are responsible for the modulation of folding and activity of the peptidase pro-enzyme or zymogen. The pro-segment docks into the enzyme, shielding the substrate binding site, thereby promoting inhibition of the enzyme. Several such propeptides share a similar topology, despite often low sequence identities.[3][4] The propeptide region has an open-sandwich antiparallel-alpha/antiparallel-beta fold, with two alpha-helices and four beta-strands with a (beta/alpha/beta)x2 topology. The peptidase inhibitor I9 family contains the propeptide domain at the N-terminus of peptidases belonging to MEROPS family S8A, subtilisins. The propeptide is removed by proteolytic cleavage; removal activating the enzyme.

Inhibitor I10[edit]

Serine endopeptidase inhibitors
PDB 1ixu EBI.jpg
solution structure of marinostatin, a protease inhibitor, containing two ester linkages
Identifiers
Symbol Inhibitor_I10
Pfam PF12559
InterPro IPR022217

This family includes both microviridins and marinostatins. It seems likely that in both cases it is the C-terminus which becomes the active inhibitor after post-translational modifications of the full length, pre-peptide. it is the ester linkages within the key, 12-residue. region that circularise the molecule giving it its inhibitory conformation.

Inhibitor I24[edit]

PinA peptidase inhibitor
Identifiers
Symbol Inhibitor_I24
Pfam PF10465
InterPro IPR019506
MEROPS I24

This family includes PinA, which inhibits the endopeptidase La. It binds to the La homotetramer but does not interfere with the ATP binding site or the active site of La.

Inhibitor I29[edit]

Cathepsin propeptide inhibitor domain (I29)
PDB 1cjl EBI.jpg
crystal structure of a cysteine protease proform
Identifiers
Symbol Inhibitor_I29
Pfam PF08246
InterPro IPR013201

The inhibitor I29 domain, which belongs to MEROPS peptidase inhibitor family I29, is found at the N-terminus of a variety of peptidase precursors that belong to MEROPS peptidase subfamily C1A; these include cathepsin L, papain, and procaricain.[5] It forms an alpha-helical domain that runs through the substrate-binding site, preventing access. Removal of this region by proteolytic cleavage results in activation of the enzyme. This domain is also found, in one or more copies, in a variety of cysteine peptidase inhibitors such as salarin.[6]

Inhibitor I34[edit]

Saccharopepsin inhibitor I34
PDB 1dp5 EBI.jpg
the structure of proteinase a complexed with a ia3 mutant inhibitor
Identifiers
Symbol Inhibitor_I34
Pfam PF10466
InterPro IPR019507
MEROPS I34

The saccharopepsin inhibitor I34 is highly specific for the aspartic peptidase saccharopepsin. In the absence of saccharopepsin it is largely unstructured,[7] but in its presence, the inhibitor undergoes a conformational change forming an almost perfect alpha-helix from Asn2 to Met32 in the active site cleft of the peptidase.

Inhibitor I36[edit]

Peptidase inhibitor family I36
PDB 1bhu EBI.jpg
the 3d structure of the streptomyces metalloproteinase inhibitor, smpi, isolated from streptomyces nigrescens tk-23, nmr, minimized average structure
Identifiers
Symbol Inhibitor_I36
Pfam PF03995
Pfam clan CL0333
InterPro IPR007141
MEROPS I36
SCOP 1bhu
SUPERFAMILY 1bhu

The peptidase inhibitor family I36 domain is only found in a small number of proteins restricted to Streptomyces species. All have four conserved cysteines that probably form two disulphide bonds. One of these proteins from Streptomyces nigrescens, is the well characterised metalloproteinase inhibitor SMPI.[8][9]

The structure of SMPI has been determined. It has 102 amino acid residues with two disulphide bridges and specifically inhibits metalloproteinases such as thermolysin, which belongs to MEROPS peptidase family M4. SMPI is composed of two beta-sheets, each consisting of four antiparallel beta-strands. The structure can be considered as two Greek key motifs with 2-fold internal symmetry, a Greek key beta-barrel. One unique structural feature found in SMPI is in its extension between the first and second strands of the second Greek key motif which is known to be involved in the inhibitory activity of SMPI. In the absence of sequence similarity, the SMPI structure shows clear similarity to both domains of the eye lens crystallins, both domains of the calcium sensor protein-S, as well as the single-domain yeast killer toxin. The yeast killer toxin structure was thought to be a precursor of the two-domain beta gamma-crystallin proteins, because of its structural similarity to each domain of the beta gamma-crystallins. SMPI thus provides another example of a single-domain protein structure that corresponds to the ancestral fold from which the two-domain proteins in the beta gamma-crystallin superfamily are believed to have evolved.[10]

Inhibitor I42[edit]

Chagasin family peptidase inhibitor I42
PDB 2fo8 EBI.jpg
solution structure of the trypanosoma cruzi cysteine protease inhibitor chagasin
Identifiers
Symbol Inhibitor_I42
Pfam PF09394
InterPro IPR018990
MEROPS I42

Inhibitor family I42 includes chagasin, a reversible inhibitor of papain-like cysteine proteases.[11] Chagasin has a beta-barrel structure, which is a unique variant of the immunoglobulin fold with homology to human CD8alpha.[12][13]

Inhibitor I48[edit]

Peptidase inhibitor clitocypin
Identifiers
Symbol Inhibitor_I48
Pfam PF10467
InterPro IPR019508
MEROPS I48

Inhibitor family I48 includes clitocypin, which binds and inhibits cysteine proteinases. It has no similarity to any other known cysteine proteinase inhibitors but bears some similarity to a lectin-like family of proteins from mushrooms.[14]

Inhibitor I53[edit]

Thrombin inhibitor Madanin
Identifiers
Symbol Inhibitor_I53
Pfam PF11714
InterPro IPR021716
MEROPS I53

Members of this family are the peptidase inhibitor madanin proteins. These proteins were isolated from tick saliva.[15]

Inhibitor I67[edit]

Bromelain inhibitor VI
PDB 1bi6 EBI.jpg
nmr structure of bromelain inhibitor vi from pineapple stem
Identifiers
Symbol Inhibitor_I67
Pfam PF11405
InterPro IPR022713
MEROPS I67

Bromelain inhibitor VI, in the Inhibitor I67 family, is a double-chain inhibitor consisting of an 11-residue and a 41-residue chain.

Inhibitor I68[edit]

Carboxypeptidase inhibitor I68
PDB 1zli EBI.jpg
crystal structure of the tick carboxypeptidase inhibitor in complex with human carboxypeptidase b
Identifiers
Symbol Inhibitor_I68
Pfam PF10468
InterPro IPR019509
MEROPS I68

The Carboxypeptidase inhibitor I68 family represents a family of tick carboxypetidase inhibitors.

Inhibitor I78[edit]

Peptidase inhibitor I78 family
Identifiers
Symbol Inhibitor_I78
Pfam PF11720
Pfam clan CL0367
InterPro IPR021719
MEROPS I78

The peptidase inhibitor I78 family includes Aspergillus elastase inhibitor.

Compounds[edit]

See also[edit]

References[edit]

  1. ^ OMIM - PROTEASE INHIBITOR 1; PI
  2. ^ Rawlings ND, Tolle DP, Barrett AJ (March 2004). "Evolutionary families of peptidase inhibitors". Biochem. J. 378 (Pt 3): 705–16. doi:10.1042/BJ20031825. PMC 1224039. PMID 14705960. 
  3. ^ Tangrea MA, Bryan PN, Sari N, Orban J (July 2002). "Solution structure of the pro-hormone convertase 1 pro-domain from Mus musculus". J. Mol. Biol. 320 (4): 801–12. doi:10.1016/S0022-2836(02)00543-0. PMID 12095256. 
  4. ^ Jain SC, Shinde U, Li Y, Inouye M, Berman HM (November 1998). "The crystal structure of an autoprocessed Ser221Cys-subtilisin E-propeptide complex at 2.0 A resolution". J. Mol. Biol. 284 (1): 137–44. doi:10.1006/jmbi.1998.2161. PMID 9811547. 
  5. ^ Groves MR, Taylor MA, Scott M, Cummings NJ, Pickersgill RW, Jenkins JA (October 1996). "The prosequence of procaricain forms an alpha-helical domain that prevents access to the substrate-binding cleft". Structure 4 (10): 1193–203. PMID 8939744. 
  6. ^ Olonen A, Kalkkinen N, Paulin L (July 2003). "A new type of cysteine proteinase inhibitor--the salarin gene from Atlantic salmon (Salmo salar L.) and Arctic charr (Salvelinus alpinus)". Biochimie 85 (7): 677–81. doi:10.1016/S0300-9084(03)00128-7. PMID 14505823. 
  7. ^ Green TB, Ganesh O, Perry K, Smith L, Phylip LH, Logan TM, Hagen SJ, Dunn BM, Edison AS (April 2004). "IA3, an aspartic proteinase inhibitor from Saccharomyces cerevisiae, is intrinsically unstructured in solution". Biochemistry 43 (14): 4071–81. doi:10.1021/bi034823n. PMID 15065849. 
  8. ^ Tanaka K, Aoki H, Oda K, Murao S, Saito H, Takahashi H (November 1990). "Nucleotide sequence of the gene for a metalloproteinase inhibitor of Streptomyces nigrescens (SMPI)". Nucleic Acids Res. 18 (21): 6433. doi:10.1093/nar/18.21.6433. PMC 332545. PMID 2243793. 
  9. ^ Murai H, Hara S, Ikenaka T, Oda K, Murao S (January 1985). "Amino acid sequence of Streptomyces metallo-proteinase inhibitor from Streptomyces nigrescens TK-23". J. Biochem. 97 (1): 173–80. PMID 3888972. 
  10. ^ Ohno A, Tate S, Seeram SS, Hiraga K, Swindells MB, Oda K, Kainosho M (September 1998). "NMR structure of the Streptomyces metalloproteinase inhibitor, SMPI, isolated from Streptomyces nigrescens TK-23: another example of an ancestral beta gamma-crystallin precursor structure". J. Mol. Biol. 282 (2): 421–33. doi:10.1006/jmbi.1998.2022. PMID 9735297. 
  11. ^ Monteiro AC, Abrahamson M, Lima AP, Vannier-Santos MA, Scharfstein J (November 2001). "Identification, characterization and localization of chagasin, a tight-binding cysteine protease inhibitor in Trypanosoma cruzi". J. Cell. Sci. 114 (Pt 21): 3933–42. PMID 11719560. 
  12. ^ Figueiredo da Silva AA, de Carvalho Vieira L, Krieger MA, Goldenberg S, Zanchin NI, Guimarães BG (February 2007). "Crystal structure of chagasin, the endogenous cysteine-protease inhibitor from Trypanosoma cruzi". J. Struct. Biol. 157 (2): 416–23. doi:10.1016/j.jsb.2006.07.017. PMID 17011790. 
  13. ^ Wang SX, Pandey KC, Scharfstein J, Whisstock J, Huang RK, Jacobelli J, Fletterick RJ, Rosenthal PJ, Abrahamson M, Brinen LS, Rossi A, Sali A, McKerrow JH (May 2007). "The structure of chagasin in complex with a cysteine protease clarifies the binding mode and evolution of an inhibitor family". Structure 15 (5): 535–43. doi:10.1016/j.str.2007.03.012. PMID 17502099. 
  14. ^ Brzin J, Rogelj B, Popovic T, Strukelj B, Ritonja A (June 2000). "Clitocypin, a new type of cysteine proteinase inhibitor from fruit bodies of mushroom clitocybe nebularis". J. Biol. Chem. 275 (26): 20104–9. doi:10.1074/jbc.M001392200. PMID 10748021. 
  15. ^ Iwanaga S, Okada M, Isawa H, Morita A, Yuda M, Chinzei Y (May 2003). "Identification and characterization of novel salivary thrombin inhibitors from the ixodidae tick, Haemaphysalis longicornis". Eur. J. Biochem. 270 (9): 1926–34. doi:10.1046/j.1432-1033.2003.03560.x. PMID 12709051. 

External links[edit]

This article incorporates text from the public domain Pfam and InterPro IPR022217

This article incorporates text from the public domain Pfam and InterPro IPR019506

This article incorporates text from the public domain Pfam and InterPro IPR013201

This article incorporates text from the public domain Pfam and InterPro IPR019507

This article incorporates text from the public domain Pfam and InterPro IPR007141

This article incorporates text from the public domain Pfam and InterPro IPR018990

This article incorporates text from the public domain Pfam and InterPro IPR019508

This article incorporates text from the public domain Pfam and InterPro IPR021716

This article incorporates text from the public domain Pfam and InterPro IPR022713

This article incorporates text from the public domain Pfam and InterPro IPR019509

This article incorporates text from the public domain Pfam and InterPro IPR021719

This article incorporates text from the public domain Pfam and InterPro IPR010259

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.

Saccharopepsin inhibitor I34 Provide feedback

The saccharopepsin inhibitor is highly specific for the aspartic peptidase saccharopepsin. It is largely unstructured in the absence of saccharopepsin [1] but in the presence, the inhibitor undergoes a conformation change forming an almost perfect alpha-helix from Asn2 to Met32 in the active site cleft of the peptidase.

Literature references

  1. Green TB, Ganesh O, Perry K, Smith L, Phylip LH, Logan TM, Hagen SJ, Dunn BM, Edison AS; , Biochemistry. 2004;43:4071-4081.: IA3, an aspartic proteinase inhibitor from Saccharomyces cerevisiae, is intrinsically unstructured in solution. PUBMED:15065849 EPMC:15065849


External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR019507

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 IA3 polypeptide of Saccharomyces cerevisiae (Baker's yeast) is an 8kDa inhibitor of the vacuolar aspartic proteinase (proteinase A or saccharopepsin, MEROPS peptidase family A1). It belongs to MEROPS inhibitor family I34, clan JA. No other aspartic proteinase has been found to be inhibited by IA3, and at least 15 aspartic proteinases related to YprA cleave IA3 as a substrate. Ligand- free IA3 has little intrinsic secondary structure, however, upon contact with proteinase A, residues 2-32 of the inhibitor become ordered and adopt a near perfect alpha-helical conformation occupying the active site cleft of the enzyme. This potent, specific interaction is directed primarily by hydrophobic interactions made by three key features in the inhibitory sequence [PUBMED:11042188].

Domain organisation

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Alignments

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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.

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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.

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Seed source: Manual
Previous IDs: none
Type: Family
Author: Mistry J
Number in seed: 2
Number in full: 7
Average length of the domain: 68.40 aa
Average identity of full alignment: 82 %
Average coverage of the sequence by the domain: 97.96 %

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 25.0 25.0
Trusted cut-off 26.1 39.4
Noise cut-off 21.4 21.3
Model length: 68
Family (HMM) version: 4
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 Inhibitor_I34 domain has been found. There are 3 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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