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

Autor: Andreas Kuglstatter, Shirley Li, Robert Crowther, Christine Lukacs, Cheryl Janson, Srinivasan Swaminathan, Stacy Remiszewski, Manish Kumar Thakur, Andrew Schutt, Rajat Pandey, Waleed Danho, Barry Goggin, Rajiv Tyagi, Saroj K. Singh, Charles Belunis, Ramachandraiah Gosu, Lin Gao, Ajith V. Kamath
Rok vydání: 2013
Předmět:
Zdroj: Acta Crystallographica Section D: Biological Crystallography
ISSN: 1399-0047
0907-4449
DOI: 10.1107/s0907444913016284
Popis: The high-resolution crystal structures of apo and peptide-bound XIAP BIR2 are presented and compared with BIR3 structures to understand their selectivity. This crystal system can be used to determine the structures of BIR2–inhibitor complexes.
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.
Databáze: OpenAIRE
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