In
medicine, protease inhibitor is often used interchangeably with
alpha 1-antitrypsin (A1AT, which is abbreviated PI for this reason).[3] A1AT is indeed the protease inhibitor most often involved in disease, namely in
alpha-1 antitrypsin deficiency.
Classification
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 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.
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
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.[5][6] 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
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.
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.[7] 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.[8]
Inhibitor I34
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,[9] 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
the 3d structure of the streptomyces metalloproteinase inhibitor, smpi, isolated from streptomyces nigrescens tk-23, nmr, minimized average structure
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.[12]
Inhibitor I42
Chagasin family peptidase inhibitor I42
solution structure of the trypanosoma cruzi cysteine protease inhibitor chagasin
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.[16]
^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.
PMID12095256.
^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.
PMID9811547.
^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.
PMID14505823.
^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.
PMID15065849.
^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.
doi:
10.1093/oxfordjournals.jbchem.a135041.
PMID3888972.
^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.
PMID9735297.
^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.
doi:
10.1242/jcs.114.21.3933.
PMID11719560.
^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.
PMID17011790.