Summary: Serine endopeptidase inhibitors
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Protease inhibitor (biology) Edit Wikipedia article
In biology and biochemistry, protease inhibitors, or antiproteases, 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). A1AT is indeed the protease inhibitor most often involved in disease, namely in alpha-1 antitrypsin deficiency.
- 1 Classification
- 2 Families
- 3 Compounds
- 4 See also
- 5 References
- 6 External links
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. 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.
Classes of proteases are:
- Aspartic protease inhibitors
- Cysteine protease inhibitors
- Metalloprotease inhibitors
- Serine protease inhibitors
- Threonine protease inhibitors
- Trypsin inhibitors
Classes of inhibitor mechanisms of action are:
- Suicide inhibitor
- Transition state inhibitor
- Protein protease inhibitor (see serpins)
- Chelating agents
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.
|Peptidase inhibitor I9|
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
|SCOPe||1gns / SUPFAM|
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. 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.
|Serine endopeptidase inhibitors|
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.
|PinA peptidase inhibitor|
|Cathepsin propeptide inhibitor domain (I29)|
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. 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.
|Saccharopepsin inhibitor I34|
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, 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.
|Peptidase inhibitor family I36|
the 3d structure of the streptomyces metalloproteinase inhibitor, smpi, isolated from streptomyces nigrescens tk-23, nmr, minimized average structure
|SCOPe||1bhu / SUPFAM|
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.
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.
|Chagasin family peptidase inhibitor I42|
solution structure of the trypanosoma cruzi cysteine protease inhibitor chagasin
Inhibitor family I42 includes chagasin, a reversible inhibitor of papain-like cysteine proteases. Chagasin has a beta-barrel structure, which is a unique variant of the immunoglobulin fold with homology to human CD8alpha.
|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.
|Thrombin inhibitor Madanin|
|Bromelain inhibitor VI|
nmr structure of bromelain inhibitor vi from pineapple stem
|Carboxypeptidase inhibitor I68|
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.
|Peptidase inhibitor I78 family|
- Calpain inhibitor I and II
- Leupeptin (N-acetyl-L-leucyl-L-leucyl-L-argininal)
- Pefabloc SC
- PMSF (phenylmethanesulfonyl fluoride)
- Trypsin inhibitors
- "antiprotease". The Free Dictionary.
- OMIM - PROTEASE INHIBITOR 1; PI
- Rawlings ND, Tolle DP, Barrett AJ (March 2004). "Evolutionary families of peptidase inhibitors". Biochem. J. 378 (Pt 3): 705â€“16. doi:10.1042/BJ20031825. PMC 1224039. PMID 14705960.
- 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): 801â€“12. doi:10.1016/S0022-2836(02)00543-0. PMID 12095256.
- 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): 137â€“44. doi:10.1006/jmbi.1998.2161. PMID 9811547.
- 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): 1193â€“203. doi:10.1016/s0969-2126(96)00127-x. PMID 8939744.
- 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): 677â€“81. doi:10.1016/S0300-9084(03)00128-7. PMID 14505823.
- 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): 4071â€“81. doi:10.1021/bi034823n. PMID 15065849.
- 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.
- 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): 173â€“80. PMID 3888972.
- 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): 421â€“33. doi:10.1006/jmbi.1998.2022. PMID 9735297.
- 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): 3933â€“42. PMID 11719560.
- Figueiredo da Silva AA; de Carvalho Vieira L; Krieger MA; Goldenberg S; Zanchin NI; GuimarÃ£es BG (February 2007). "Crystal structure of chagasin, the endogenous cysteine-protease inhibitor from Trypanosoma cruzi". J. Struct. Biol. 157 (2): 416â€“23. doi:10.1016/j.jsb.2006.07.017. PMID 17011790.
- 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): 535â€“43. doi:10.1016/j.str.2007.03.012. PMID 17502099.
- 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): 20104â€“9. doi:10.1074/jbc.M001392200. PMID 10748021.
- 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): 1926â€“34. doi:10.1046/j.1432-1033.2003.03560.x. PMID 12709051.
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.
Serine endopeptidase inhibitors Provide feedback
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 [1, 2, 3].
Miyamoto K, Tsujibo H, Hikita Y, Tanaka K, Miyamoto S, Hishimoto M, Imada C, Kamei K, Hara S, Inamori Y;, Biosci Biotechnol Biochem. 1998;62:2446-2449.: Cloning and nucleotide sequence of the gene encoding a serine proteinase inhibitor named marinostatin from a marine bacterium, Alteromonas sp. strain B-10-31. PUBMED:9972273 EPMC:9972273
This tab holds annotation information from the InterPro database.
InterPro entry 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.
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
- the number of sequences which exhibit this architecture
a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
This example describes an architecture with one
Gladomain, followed by two consecutive
EGFdomains, and finally a single
- a link to the page in the Pfam site showing information about the sequence that the graphic describes
- the UniProt description of the protein sequence
- the number of residues in the sequence
- the Pfam graphic itself.
Note that you can see the family page for a particular domain by clicking on the graphic. You can also choose to see all sequences which have a given architecture by clicking on the Show link in each row.
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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 (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets and the UniProtKB sequence database. More...
There are various ways to view or download the sequence alignments that we store. We provide several sequence viewers and a plain-text Stockholm-format file for download.
We make a range of alignments for each Pfam-A family:
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- Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
- alignment generated by searching the UniProtKB sequence database using the family HMM
You can see the alignments as HTML or in three different sequence viewers:
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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.
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
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.
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
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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.
|Number in seed:||5|
|Number in full:||99|
|Average length of the domain:||53.50 aa|
|Average identity of full alignment:||35 %|
|Average coverage of the sequence by the domain:||75.85 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 57096847 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||10|
|Download:||download the raw HMM for this family|
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- 0 sequences
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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
Colouring and labels
Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
Anomalies in the taxonomy tree
There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
Missing taxonomic levels
Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
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Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.
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_I10 domain has been found. There are 11 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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