Structural basis of caspase-7 inhibition by XIAP.
The inhibitor of apoptosis (IAP) proteins suppress cell death by inhibiting the catalytic activity of caspases. Here we present the crystal structure of caspase-7 in complex with a potent inhibitory fragment from XIAP at 2.45 A resolution. An 18-residue XIAP peptide binds the catalytic groove of caspase-7, making extensive contacts to the residues that are essential for its catalytic activity. Strikingly, despite a reversal of relative orientation, a subset of interactions between caspase-7 and XIAP closely resemble those between caspase-7 and its tetrapeptide inhibitor DEVD-CHO. Our biochemical and structural analyses reveal that the BIR domains are dispensable for the inhibition of caspase-3 and -7. This study provides a structural basis for the design of the next-generation caspase inhibitors.
Department of Molecular Biology, Princeton University, Lewis Thomas Laboratory, Washington Road, Princeton, NJ 08544, USA.
J
J
Chai
E
E
Shiozaki
S M
SM
Srinivasula
Q
Q
Wu
P
P
Datta
E S
ES
Alnemri
Y
Y
Shi
P
P
Dataa
D017209:Apoptosis / Q000502:physiology; D002352:Carrier Proteins; D053179:Caspase 7; D020169:Caspases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D020134:Catalytic Domain; D024101:Mitochondrial Proteins; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D051636:X-Linked Inhibitor of Apoptosis Protein
D002352:Carrier Proteins; D024101:Mitochondrial Proteins; D011506:Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; D053179:Caspase 7; D020169:Caspases