The three-dimensional structure of apopain/CPP32, a key mediator of apoptosis.
Cysteine proteases related to mammalian interleukin-1 beta converting enzyme (ICE) and to its Caenorhabditis elegans homologue, CED-3, play a critical role in the biochemical events that culminate in apoptosis. We have determined the three-dimensional structure of a complex of the human CED-3 homologue CPP32/apopain with a potent tetrapeptide-aldehyde inhibitor. The protein resembles ICE in overall structure, but its S4 subsite is strikingly different in size and chemical composition. These differences account for the variation in specificity between the ICE- and CED-3-related proteases and enable the design of specific inhibitors that can probe the physiological functions of the proteins and disease states with which they are associated.
Rotonda
J
J
Department of Biochemistry, Merck Research Laboratories, Rahway, New Jersey 07065-0900, USA.
Nicholson
D W
DW
Fazil
K M
KM
Gallant
M
M
Gareau
Y
Y
Labelle
M
M
Peterson
E P
EP
Rasper
D M
DM
Ruel
R
R
Vaillancourt
J P
JP
Thornberry
N A
NA
Becker
J W
JW
D000595:Amino Acid Sequence; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases; D002384:Catalysis; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000737:chemistry*; D004792:Enzyme Precursors / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D007527:Isoenzymes / Q000737:chemistry; D008961:Models, Structural; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity
D004792:Enzyme Precursors; D007527:Isoenzymes; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases