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3-D Structure of Granzyme B - Inhibitor Complex Reveals Protease Specificity

 
  September, 11 2000 7:30
your information resource in human molecular genetics
 
     
Being picky

Cell death is not always a bad thing. In fact it is essential to keep tumor or virally infected cells in check. Within our bodies, cytotoxic lymphocytes can kill these undesirable cells because they are armed with molecules called 'granzymes'. These processing enzymes (proteases) work by recognizing a longer form of a protein (pro-protein) and cutting off part of it. In the case of granzymes, this cleavage reaction leads to activation of a group of enzymes known as 'caspases'. Caspases comprise a family of proteases some of whose members are involved in apoptosis (programmed cell death).

While most proteases are specific for a particular protein or substrate, granzyme B has two unique requirements. Its substrate needs to be extended, that is, not highly structured and a specific amino acid (aspartic acid) must be located next to the site of cleavage. The molecular basis of this remarkable specificity is now revealed in the three-dimensional structure of granzyme B in complex with an inhibitor.

Sandra Waugh, Charles Craik and coworkers at the University of California, San Francisco, USA show that the essential aspartic acid of the substrate fits into a pocket of granzyme B where the cleavage reaction occurs Nature Structural Biology (Vol 7, No. 9, September 2000). In addition, there are a number of distinct sites on the surface of the protease that make specific contacts with the substrate. Interestingly, some of these same sites can be found throughout the subfamily of serine proteases. This suggests that it may be possible to predict the specificity of a protease by looking at its amino acid sequence.

Contact information:

Dr. Charles S. Craik
Department of Pharmaceutical Chemistry
And the Department of Biochemistry and Biophysics
University of California
San Francisco
California 94143-0446
USA
Tel: 415 476 9890
Fax: 415 502-8298
Email: craik@cgl.ucsf.edu

Sandra M. Waugh
The Graduate Group in Biophysics
University of California
San Francisco
California 94143-0446
USA
Tel: 415 476-6757
Fax: 415 502-8298
Email: waugh@mutant.ucsf.edu

(C) Nature Structural Biology press release.


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