The structure of XIAP BIR2: understanding the selectivity of the BIR domains

Abstract

XIAP, a member of the inhibitor of apoptosis family of proteins, is a critical regulator of apoptosis. Inhibition of the BIR domain-caspase interaction is a promising approach towards treating cancer. Previous work has been directed towards inhibiting the BIR3-caspase-9 interaction, which blocks the intrinsic apoptotic pathway; selectively inhibiting the BIR2-caspase-3 interaction would also block the extrinsic pathway. The BIR2 domain of XIAP has successfully been crystallized; peptides and small-molecule inhibitors can be soaked into these crystals, which diffract to high resolution. Here, the BIR2 apo crystal structure and the structures of five BIR2-tetrapeptide complexes are described. The structural flexibility observed on comparing these structures, along with a comparison with XIAP BIR3, affords an understanding of the structural elements that drive selectivity between BIR2 and BIR3 and which can be used to design BIR2-selective inhibitors.

Targeting the Inhibitor of Apoptosis Protein BIR3 Binding Domains

“…The ability of XIAP BIR2 to accommodate a serine residue suggests the potential for selective inhibition. XIAP BIR2/BIR3 selectivity is beyond the scope of this discussion, but is the topic of several recent synthetic and crystallographic studies [14][15][16][17].…”

Bivalent SMAC Mimetics for Treating Cancer by Antagonizing Inhibitor of Apoptosis Proteins

“…XIAP BIR3 not only can bind to the IBM (IAP binding motif) of processed caspase‐9 at its N‐terminal, but also can prevent the dimerization of caspase‐9 by covering the dimerization interface via helix distal of BIR3 . The BIR2 domain of XIAP (residues 163–234) comprises a 3‐stranded antiparallel β‐sheet surrounded by five α‐helices and a zinc atom . While it is actually the linker (residues 124–162) between BIR1 and BIR2 that allows XIAP to inhibit caspases‐3 and ‐7, BIR2 strengthens and stabilizes linker binding to these enzymes .…”

“…[28][29][30] The BIR2 domain of XIAP (residues 163-234) comprises a 3-stranded antiparallel β-sheet surrounded by five α-helices and a zinc atom. [31,32] actually the linker (residues 124-162) between BIR1 and BIR2 that allows XIAP to inhibit caspases-3 and -7, BIR2 strengthens and stabilizes linker binding to these enzymes. [33][34][35] The BIR1 domain of XIAP (residues 22-99) has a structure similar to that of BIR2 and BIR3, and it mediates XIAP self-dimerization.…”

<p>The TwistDock workflow for evaluation of bivalent Smac mimetics targeting XIAP</p>

“…Over-expression of XIAP in some tumor cell lines blocks the apoptosis pathways and diminishes the efficacy of chemotherapy and radiotherapy 2,4,21. Monovalent Smac mimetics compete with only caspase-9 for XIAP and ignore the interaction of BIR2 with caspase-3/-7; thus, they are generally less potent than bivalent Smac mimetics 6,17,19,27. Attributed to the simultaneous inhibition of caspase-3, -7 and -9,28,29 bivalent Smac mimetics become attractive.…”