International Protease Network

Department of Immunology
The Weizmann Institute of Science
Rehovot 76100, Israel
Email: israel.schechter@weizmann.ac.il
Tel: 972 8 934 3631
Fax: 972 8 934 4141
Homepage:

Research

At the beginning of my scientific career I was interested in the active sites of proteolytic enzymes and antibodies. At early stages of the research (1960s) it was realized that the size of the active site of proteases was larger than expected, and we proposed a model of active site divided into subsites. For several decades this model has been used to present the specificity of proteases, using the nomenclature of Schechter & Berger from 1967 (S1, S2…for subsites of the active site; P1, P2…for residues of the substrate occupying the corresponding subsites). A procedure to map the active site was developed. The map provides information on the size of the active site (number of subsites), the properties of each subsite (free energy of ligand binding, nature of binding forces, etc.), and it enables rational design of new substrates and inhibitors. Already in 1968 inhibitors with binding constants ten thousand fold higher than available inhibitors, were prepared. The model of a large active site was initially met with strong opposition. Before long, however, predictions of the model (size of the active site, interactions in subsites remote from the catalytic site) were confirmed by X-ray crystallography (1970). During the 1990s it was found that proteolytic enzymes were involved in the pathogenesis of many diseases, they became therapeutic targets, and protease inhibitors were successfully applied in the treatment of AIDS and hypertension. The model of large active site divided into subsites, proposed 39 years ago, stood the test of time. This model is still in use in basic research to study enzyme-ligand interaction, and in pharmaceutical research for the development of inhibitors/drugs. I had not been involved in enzymology for a long period of time (in favour of molecular biology), but recently I renewed my interest in proteases and inhibitors in biology and medicine.

Collaborations

Publications

Schechter, I.; Berger, A. "On the Size of the Active Site in Proteases. I. Papain", Biochem. Biophys. Res. Comun. 1967, 27, 157-162.

Abramowitz, N.; Schechter, I.; Berger, A. "On the Size of the Active Site in Proteases. II. Carboxypeptidase-A", Biochem. Biophys. Res. Commun. 1967, 29, 862-867.

Schechter, I.; Berger, A. "On the Active Size of Proteases. III. Mapping the Active Site of Papain; Specific Peptide Inhibitors of Papain", Biochem. Biophys. Res. Commun. 1968, 32, 898-902.

Berger, A.; Schechter, I. "Mapping the Active Site of Papain with the Aid of Peptide Substrates and Inhibitors", Phil. Trans. Roy. Soc. Lond. 1970, B257, 249-264.

Schechter, I. "Mapping of the Active Site of Proteases in the 1960s and Rational Design of Inhibitors/Drugs in the 1990s", Current Protein and Peptide Science 2005, 6, 501-512.