The structure of the pro-apoptotic protease granzyme B reveals the molecular determinants of its specificity.
Granzyme B is a serine protease of the chymotrypsin fold that mediates cell death by cytotoxic lymphocytes. It is a processing enzyme, requiring extended peptide substrates containing an Asp residue. The determinants that allow for this substrate specificity are revealed in the three-dimensional structure of granzyme B in complex with a macromolecular inhibitor. The primary specificity for Asp occurs through a side-on interaction with Arg 226, a buried Arg side chain of granzyme B. An additional nine amino acids make contact with the substrate and define the granzyme B extended substrate specificity profile. The substrate determinants found in this structure are shared by other members of this protein class and help to reveal the properties that define substrate specificity.
Waugh
S M
SM
The Graduate Group in Biophysics, University of California, San Francisco, California 94143-0446, USA. waugh@mutant.ucsf.edu
Harris
J L
JL
Fletterick
R
R
Craik
C S
CS
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D017209:Apoptosis; D001224:Aspartic Acid / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D029968:Escherichia coli Proteins; D006031:Glycosylation; D053804:Granzymes; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D033903:Periplasmic Proteins; D011487:Protein Conformation; D051381:Rats; D016415:Sequence Alignment; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity
D001426:Bacterial Proteins; C039076:Eco protein, E coli; D029968:Escherichia coli Proteins; D033903:Periplasmic Proteins; D015842:Serine Proteinase Inhibitors; D001224:Aspartic Acid; C509213:GZMB protein, human; D053804:Granzymes; C509215:Gzmb protein, rat; D012697:Serine Endopeptidases