Last modified 25th May '95 © Birkbeck College 1995

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Inhibition

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.

2ci2 chymotrypsin inhibitor from barley seeds

2ssi 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)

Trypsin inhibitors

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

1tab bovine pancreatic trypsin complex with Bowman-Birk inhibitor from Adzuki beans

2ptc bovine pancreatic ß-trypsin with inhibitor

3tpi trypsinogen with BPTI

1tpa anhydro-trypsin complexed with inhibitor; from bovine pancreas

Alpha-1 antitrypsin

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

4cpa bovine pancreatic carboxypeptidase alpha complex with carboxypeptidase A inhibitor from potato 4cpa and 1cpb with inhibitor carboxypeptidase-A

Inhibitors of glycosidases

1hoe tendamistat (alpha-amylase inhibitor from Streptomyces tendae);

References

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J. Walshaw