Inbiology andbiochemistry,protease inhibitors, orantiproteases,[1] aremolecules that inhibit the function ofproteases (enzymes that aidthe breakdown of proteins). Many naturally occurring protease inhibitors areproteins.[2]
Inmedicine,protease inhibitor is often used interchangeably withalpha 1-antitrypsin (A1AT, which is abbreviated PI for this reason).[3] A1AT is indeed the protease inhibitor most often involved in disease, namely inalpha-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.[4] This classification initially identified 48 families of inhibitors that could be grouped into 26 related superfamily (or clans) by their structure. According to theMEROPS database there are now 81 families of inhibitors. These families are named with an I followed by a number, for example, I14 containshirudin-like inhibitors.
Classes ofproteases are:
Classes ofinhibitor mechanisms of action are:
This is a family of proteasesuicide inhibitors called theserpins. It contains inhibitors of multiple cysteine and serine protease families. Their mechanism of action relies on undergoing a largeconformational change which inactivates their target'scatalytic 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 | |||||||||
| Identifiers | |||||||||
| Symbol | Inhibitor_I9 | ||||||||
| Pfam | PF05922 | ||||||||
| InterPro | IPR010259 | ||||||||
| MEROPS | I9 | ||||||||
| SCOP2 | 1gns /SCOPe /SUPFAM | ||||||||
| |||||||||
Proteinase propeptide inhibitors (sometimes referred to as activation peptides) are responsible for the modulation offolding and activity of the peptidase pro-enzyme orzymogen. The pro-segment docks into the enzyme, shielding thesubstrate binding site, thereby promoting inhibition of the enzyme. Several such propeptides share a similar topology, despite often lowsequence identities.[5][6] The propeptide region has an open-sandwich antiparallel-alpha/antiparallel-beta fold, with twoalpha-helices and fourbeta-strands with a (beta/alpha/beta)x2 topology.The peptidase inhibitor I9 family contains the propeptide domain at theN-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 | |||||||||
| Identifiers | |||||||||
| Symbol | Inhibitor_I10 | ||||||||
| Pfam | PF12559 | ||||||||
| InterPro | IPR022217 | ||||||||
| |||||||||
This family includes bothmicroviridins and marinostatins. It seems likely that in both cases it is theC-terminus which becomes the activeinhibitor afterpost-translational modifications of the full length, pre-peptide. It is theester linkages within the key, 12-residue region that circularise themolecule giving it its inhibitoryconformation.
| PinA peptidase inhibitor | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
| Symbol | Inhibitor_I24 | ||||||||
| Pfam | PF10465 | ||||||||
| InterPro | IPR019506 | ||||||||
| MEROPS | I24 | ||||||||
| |||||||||
This family includes PinA, whichinhibits theendopeptidase La. It binds to the Lahomotetramer but does not interfere with theATPbinding site or the active site of La.
| Cathepsin propeptide inhibitor domain (I29) | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 crystal structure of a cysteine protease proform | |||||||||
| Identifiers | |||||||||
| Symbol | Inhibitor_I29 | ||||||||
| Pfam | PF08246 | ||||||||
| InterPro | IPR013201 | ||||||||
| |||||||||
The inhibitor I29domain, which belongs to MEROPS peptidase inhibitor family I29, is found at theN-terminus of a variety ofpeptidase precursors that belong to MEROPS peptidase subfamily C1A; these includecathepsin L,papain, and procaricain.[7] It forms analpha-helical domain that runs through the substrate-binding site, preventing access. Removal of this region byproteolytic cleavage results in activation of theenzyme. This domain is also found, in one or more copies, in a variety of cysteine peptidase inhibitors such as salarin.[8]
| Saccharopepsin inhibitor I34 | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 the structure of proteinase a complexed with an ia3 mutant inhibitor | |||||||||
| Identifiers | |||||||||
| Symbol | Inhibitor_I34 | ||||||||
| Pfam | PF10466 | ||||||||
| InterPro | IPR019507 | ||||||||
| MEROPS | I34 | ||||||||
| |||||||||
The saccharopepsininhibitor I34 is highly specific for the aspartic peptidase saccharopepsin. In the absence of saccharopepsin it is largely unstructured,[9] but in its presence, theinhibitor undergoes aconformational change forming an almost perfectalpha-helix fromAsn2 toMet32 in theactive 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 | |||||||||
| Identifiers | |||||||||
| Symbol | Inhibitor_I36 | ||||||||
| Pfam | PF03995 | ||||||||
| Pfam clan | CL0333 | ||||||||
| InterPro | IPR007141 | ||||||||
| MEROPS | I36 | ||||||||
| SCOP2 | 1bhu /SCOPe /SUPFAM | ||||||||
| |||||||||
The peptidase inhibitor family I36 domain is only found in a small number ofproteins restricted toStreptomycesspecies. All have fourconservedcysteines that probably form twodisulphide bonds. One of theseproteins fromStreptomyces nigrescens, is the well characterised metalloproteinaseinhibitor SMPI.[10][11]
Thestructure of SMPI has been determined. It has 102amino acid residues with two disulphide bridges and specificallyinhibits metalloproteinases such asthermolysin, which belongs to MEROPSpeptidase family M4. SMPI is composed of twobeta-sheets, each consisting of fourantiparallel beta-strands. The structure can be considered as two Greek key motifs with 2-fold internal symmetry, a Greek keybeta-barrel. One uniquestructural 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 SMPIstructure shows clear similarity to bothdomains of the eye lenscrystallins, bothdomains of the calcium sensor protein-S, as well as the single-domainyeast killertoxin. The yeast killer toxin structure was thought to be aprecursor 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 ancestralfold from which the two-domain proteins in the beta gamma-crystallinsuperfamily are believed to haveevolved.[12]
| Chagasin family peptidase inhibitor I42 | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 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 ofpapain-likecysteine proteases.[13] Chagasin has abeta-barrel structure, which is a unique variant of theimmunoglobulin fold withhomology tohumanCD8alpha.[14][15]
| Peptidase inhibitor clitocypin | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
| Symbol | Inhibitor_I48 | ||||||||
| Pfam | PF10467 | ||||||||
| InterPro | IPR019508 | ||||||||
| MEROPS | I48 | ||||||||
| |||||||||
Inhibitor family I48 includes clitocypin, which binds andinhibits cysteine proteinases. It has no similarity to any other known cysteine proteinase inhibitors but bears some similarity to alectin-likefamily of proteins frommushrooms.[16]
| Thrombin inhibitor Madanin | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
| Symbol | Inhibitor_I53 | ||||||||
| Pfam | PF11714 | ||||||||
| InterPro | IPR021716 | ||||||||
| MEROPS | I53 | ||||||||
| |||||||||
Members of this family are thepeptidaseinhibitor madaninproteins. Theseproteins were isolated fromticksaliva.[17]
| Bromelain inhibitor VI | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 nmr structure of bromelain inhibitor vi from pineapple stem | |||||||||
| Identifiers | |||||||||
| Symbol | Inhibitor_I67 | ||||||||
| Pfam | PF11405 | ||||||||
| InterPro | IPR022713 | ||||||||
| MEROPS | I67 | ||||||||
| |||||||||
Bromelaininhibitor VI, in the Inhibitor I67 family, is a double-chaininhibitor consisting of an 11-residue and a 41-residuechain.
| Carboxypeptidase inhibitor I68 | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 crystal structure of the tick carboxypeptidase inhibitor in complex with humancarboxypeptidase B | |||||||||
| Identifiers | |||||||||
| Symbol | Inhibitor_I68 | ||||||||
| Pfam | PF10468 | ||||||||
| InterPro | IPR019509 | ||||||||
| MEROPS | I68 | ||||||||
| |||||||||
The Carboxypeptidase inhibitor I68 family represents a family ofcarboxypeptidase inhibitors found inticks.[18]
| Peptidase inhibitor I78 family | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
| Symbol | Inhibitor_I78 | ||||||||
| Pfam | PF11720 | ||||||||
| Pfam clan | CL0367 | ||||||||
| InterPro | IPR021719 | ||||||||
| MEROPS | I78 | ||||||||
| |||||||||
The peptidase inhibitor I78 family includesAspergilluselastaseinhibitor.
