Last modified 25th May '95 © Birkbeck College 1995
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This section is concerned (mostly) with inhibitors which are themselves
proteins; many enzyme-inhibitors are of course small molecules.
There follows a brief survey of some of the inhibitor proteins
for which the structures are known.
Compare the structures of the different inhibitors- how similar are the
proteins which inhibit the same kinds of active sites?
Inhibitors of serine proteases (e.g. trypsin, chymotrypsin, elastase)
The structures of a number of serine protease inhibitors have been solved;
in addition there are several complexes of these inhibitors with the enzymes.
Some of these involve enzymes and inhibitors from different species, which in
some cases relate to the lifestyle of the organism- e.g., bloodsucking animals
such as leeches produce factors which suppress blood coagulation of the host,
by inhibiting enzymes of the clotting pathway such as thrombin.
chymotrypsin inhibitor from barley seeds
subtilisin inhibitor from Streptomyces albogriseolus
1cse subtilisin carlsberg (a serine proteinase) from Bacillus subtilis
and elastase inhibitor from leech
2hir hirudin, a thrombin inhibitor (i.e. a coagulation inhibitor; produced by leech); NMR
1tec Thermitase (Thermoactinomyces vulgaris) with eglin-C (leech)
2kai kallikrein A, a specific trypsin-like serine protease, complexed with BPTI
3sgb proteinase B from Streptomyces griseus complex with third domain of turkey ovomucoid inhibitor
1cho chymotrypsin complexed with ovomucoid third domain
1pce PEC-60 Kazal type proteinase inhibitor
1bus proteinase inhibitor IIa from bull seminal plasma (NMR)
1pi2 soybean trypsin inhibitor;
1cti Cucurbita maxima trypsin inhibitor;
1tieErythrina caffra trypsin inhibitor;
2ovo third domain of ovomucoid, a Kazal-type trypsin inhibitor;
1aap trypsin inhibitor domain of alzheimer's amyloid beta-protein precursor
bovine pancreatic trypsin complex with Bowman-Birk
inhibitor from Adzuki beans
2ptc bovine pancreatic ß-trypsin with inhibitor
3tpi trypsinogen with BPTI
anhydro-trypsin complexed with inhibitor;
from bovine pancreas
In the active inhibitor, residues Met 358 and Ser 359 are
covalently linked. Cleavage of this peptide bond results in a
major conformational rearrangement, after which the two
residues are approximately 67Å apart. See REMARK 4
in the pdb files (7api, 8api, 9api) and Loebermann
et al. (1984).
7api modified forms of human alpha-1 antitrypsin
(Peptide) Inhibitors of aspartic proteases
3phv HIV-1 protease (a dimeric acid protease) with
hydroxyethylamine inhibitor ;
1phv diagram of model structure of HIV-1 protease dimer with acetyl-pepstatin inhibitor
3apr peptide inhibitor with aspartic proteinase (Rhizopus chinensis)
Inhibitors of carboxypeptidases
bovine pancreatic carboxypeptidase alpha complex with carboxypeptidase
A inhibitor from potato
4cpa and 1cpb with inhibitor
Inhibitors of glycosidases
1hoe tendamistat (alpha-amylase inhibitor from
- Bode, W., Papamakos, E. and Musil, D. (1987)The high-resolution
X-ray crystal structure of the complex formed between subtilisin Carlsberg
and eglin c, an elastase inhibitor from the leech Hirudo medicinalis.
Structural analysis, subtilisin structure and interface geometry.
Eur. J. Biochem. 166, 673-692
- Chen, Z. and Bode, W. (1983) Refined 2.5 A X-ray crystal structure
of the complex formed by porcine kallikrein A and the bovine pancreatic
trypsin inhibitor. Crystallization, Patterson search, structure
determination, refinement, structure and comparison with its components
and with the bovine trypsin-pancreatictrypsin inhibitor complex.
J. Mol. Biol., 164, 283-311
- Fitzgerald,P.M., McKeever, B.M, VanMiddlesworth, J. F., Springer, J.C.,
Heimbach,J. C., Leu, C. T., Herber, W.K., Dixon, R. A., and Darke, P.L. (1990)
Crystallographic analysis of a complex between human immunodeficiency virus type 1 protease and
acetyl-pepstatin at 2.0-Å resolution.
J. Biol. Chem. 265, 14209-14219
- Folkers, P.J., Clore, G.M., Driscoll, P.C., Dodt,J. Kohler, S.
and Gronenborn, A. M. (1989) Solution structure of recombinant
hirudin and the Lys-47----Glu mutant: a nuclear magnetic resonance
and hybrid distance geometry-dynamical simulated annealing study.
Biochemistry 28, 2601-2617
- Fujinaga, M., Sielecki, A.R., Read, R.J., Ardelt, W., Laskowski, M.
and James, M.N. (1987) Crystal and molecular structures of the complex
of alpha-chymotrypsin with its inhibitor turkey ovomucoid third domain at
J. Mol. Biol.195, 397-418
- Gustchina, A. and Weber, I.T. (1991) Comparative analysis of the sequences
and structures of HIV-1 and HIV-2 proteases.
Proteins 10, 325-339
- Huber, R., Kukla, D., Bode, W., Schwager, P., Bartels, K., Deisenhofer, J.
and Steigema, W. (1974) Structure of the complex formed by bovine trypsin and bovine pancreatic trypsin inhibitor. II.
Crystallographic refinement at 1.9Å resolution.
J. Mol. Biol. 89, 73-101
- Loebermann, H., Tokuoka, R., Deisenhofer, J. and Huber, R. (1984)
Human alpha 1-proteinase inhibitor. Crystal structure analysis of two
crystal modifications, molecular model and preliminary analysis of the
implications for function.
J. Mol. Biol.177, 531-557
- Mosolov, V.V. (1995) Protein inhibitors of proteinases and alpha-amylases
in plants (a review) Applied Biochemistry and Microbiology
31 , 3-7
- Pflugrath, J.W., Wiegand, G., Huber, R. and Vertesy, L. (1986)
Crystal structure determination, refinement and the molecular model of the alpha-amylase inhibitor
J. Mol. Biol. 189, 383-386
- Read, R.J., Fujinaga, M., Sielecki, A.R. and James ,M. N. (1983)
Structure of the complex of Streptomyces griseus protease B and the third
domain of the turkey ovomucoid inhibitor at 1.8-Å resolution.
- Rees, D.C. and Lipscombe, W.N. (1982) Refined crystal structure of the
potato inhibitor complex of carboxypeptidase A at 2.5Å resolution.
J. Mol. Biol. 170, 475-498
- Suguna, K., Padlan, E.A., Smith, C.W., Carlson, W.D. and Davies, D.R.(1987)
inding of a reduced peptide inhibitor to the aspartic proteinase from Rhizopus chinensis:
implications for a mechanism of action.
Proc. Natl. Acad. Sci. USA 84, 7009-7013
- Tsunogae, Y., Tanaka, I., Yamane, T., Kikkawa, J., Ashida, T., Ishikawa, C.,
Watanabe, K., Nakamura, S. and Takahashi, K. (1986) Structure of the
trypsin-binding domain of Bowman-Birk type protease inhibitor and its interaction
J. Biochem. (Tokyo) 100, 1637-1646
- Williamson, M. P., Havel, T. F. and Wuthrich ,K. (1985) Solution
conformation of proteinase inhibitor IIA from bull seminal plasma by
1H nuclear magnetic resonance and distance geometry.
J. Mol. Biol.182, 295-315
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