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

作者：Lukacs Christine^*; Belunis Charles; Crowther Robert; Danho Waleed; Gao Lin; Goggin Barry; Janson Cheryl A; Li Shirley; Remiszewski Stacy; Schutt Andrew; Thakur Manish K; Singh Saroj K; Swaminathan Srinivasan; Pandey Rajat; Tyagi Rajiv; Gosu Ramachandraiah; Kamath Ajith V; Kuglstatter Andreas

来源：Acta Crystallographica Section D-Biological Crystallography, 2013, 69(9): 1717-1725.

DOI：10.1107/S0907444913016284

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.

• 出版日期2013-9