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1  structure 569  species 0  interactions 1566  sequences 44  architectures

Family: Inhibitor_I36 (PF03995)

Summary: Peptidase inhibitor family I36

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, or antiproteases,[1] are molecules that inhibit the function of proteases (enzymes that aid the breakdown of proteins). 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).[2] A1AT is indeed the protease inhibitor most often involved in disease, namely in alpha-1 antitrypsin deficiency.


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.[3] 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 81 families of inhibitors. These families are named with an I followed by a number, for example, I14 contains hirudin-like inhibitors.

By protease

Classes of proteases are:

By mechanism

Classes of inhibitor mechanisms of action are:


Inhibitor I4

This is a family of protease suicide inhibitors called the serpins. It contains inhibitors of multiple cysteine and serine protease families. Their mechanism of action relies on undergoing a large conformational change which inactivates their target's catalytic triad.

Inhibitor I9

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

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.[4][5] 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

Serine endopeptidase inhibitors
PDB 1ixu EBI.jpg
solution structure of marinostatin, a protease inhibitor, containing two ester linkages

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

PinA peptidase inhibitor

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

Cathepsin propeptide inhibitor domain (I29)
PDB 1cjl EBI.jpg
crystal structure of a cysteine protease proform

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.[6] 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.[7]

Inhibitor I34

Saccharopepsin inhibitor I34
PDB 1dp5 EBI.jpg
the structure of proteinase a complexed with an ia3 mutant inhibitor

The saccharopepsin inhibitor I34 is highly specific for the aspartic peptidase saccharopepsin. In the absence of saccharopepsin it is largely unstructured,[8] 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

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
Pfam clanCL0333

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.[9][10]

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.[11]

Inhibitor I42

Chagasin family peptidase inhibitor I42
PDB 2fo8 EBI.jpg
solution structure of the trypanosoma cruzi cysteine protease inhibitor chagasin

Inhibitor family I42 includes chagasin, a reversible inhibitor of papain-like cysteine proteases.[12] Chagasin has a beta-barrel structure, which is a unique variant of the immunoglobulin fold with homology to human CD8alpha.[13][14]

Inhibitor I48

Peptidase inhibitor clitocypin

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.[15]

Inhibitor I53

Thrombin inhibitor Madanin

Members of this family are the peptidase inhibitor madanin proteins. These proteins were isolated from tick saliva.[16]

Inhibitor I67

Bromelain inhibitor VI
PDB 1bi6 EBI.jpg
nmr structure of bromelain inhibitor vi from pineapple stem

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

Carboxypeptidase inhibitor I68
PDB 1zli EBI.jpg
crystal structure of the tick carboxypeptidase inhibitor in complex with human carboxypeptidase b

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

Inhibitor I78

Peptidase inhibitor I78 family
Pfam clanCL0367

The peptidase inhibitor I78 family includes Aspergillus elastase inhibitor.


See also


  1. ^ "antiprotease". The Free Dictionary.
  3. ^ 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.
  4. ^ 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.
  5. ^ 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.
  6. ^ 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. doi:10.1016/s0969-2126(96)00127-x. PMID 8939744.
  7. ^ 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.
  8. ^ 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.
  9. ^ 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.
  10. ^ 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.
  11. ^ 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.
  12. ^ 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.
  13. ^ 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.
  14. ^ 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.
  15. ^ 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.
  16. ^ 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

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

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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.

Peptidase inhibitor family I36 Provide feedback

This domain is currently only found in a small set of S. coelicolor secreted proteins. There are four conserved cysteines that probably form two disulphide bonds. Proteins 2SCK31.15C (Q9ADK5) and SCO3675 (Q9X8V7) also have probable beta-propellers at their C-termini. This family includes P01077 a known peptidase inhibitor of known structure. This protein has a crystallin like fold PF00030 and is distantly related by sequence. It is not known whether other members of this family are peptidase inhibitors.

Literature references

  1. Yeats C, Bentley S, Bateman A; , BMC Microbiol 2003;3:3-3.: New Knowledge from Old: In silico discovery of novel protein domains in Streptomyces coelicolor. PUBMED:12625841 EPMC:12625841

  2. Ohno A, Tate S, Seeram SS, Hiraga K, Swindells MB, Oda K, Kainosho M; , J Mol Biol 1998;282:421-433.: NMR structure of the Streptomyces metalloproteinase inhibitor, SMPI, isolated from Streptomyces nigrescens TK-23: another example of an ancestral beta gamma-crystallin precursor structure. PUBMED:9735297 EPMC:9735297

Internal database links

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This tab holds annotation information from the InterPro database.

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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 gCrystallin (CL0333), which has the following description:

This superfamily includes a number of mammalian crystallins as well as ancestral beta gamma-crystallin precursor structures.

The clan contains the following 8 members:

Crystall Crystall_2 Crystall_3 Crystall_4 IL4_i_Ig Inhibitor_I36 MiAMP1 Yeast-kill-tox


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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.

Curation View help on the curation process

Seed source: Yeats C, Bateman A
Previous IDs: DUF351;
Type: Domain
Sequence Ontology: SO:0000417
Author: Yeats C , Bateman A
Number in seed: 37
Number in full: 1566
Average length of the domain: 72.80 aa
Average identity of full alignment: 18 %
Average coverage of the sequence by the domain: 40.17 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 57096847 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 21.1 21.1
Trusted cut-off 21.1 21.1
Noise cut-off 21.0 21.0
Model length: 69
Family (HMM) version: 15
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Archea Archea Eukaryota Eukaryota
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Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence


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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 Inhibitor_I36 domain has been found. There are 1 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 sequence.

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AlphaFold Structure Predictions

The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.

Protein Predicted structure External Information
Q54F49 View 3D Structure Click here