One way to inhibit apoptosis is by blocking the activity of caspases, a job done by the inhibitor of apoptosis (IAP) proteins. Last year saw the identification of a mitochondrial protein called Smac/DIABLO, which has the opposite effect — it counters the inhibitory effects of IAPs by physically interacting with them. The structural basis of this interaction is discussed by two papers in Nature, and the results might have implications for the design of small molecules to treat cancer.

Liu and colleagues solved the solution structure of the BIR3 domain of one IAP (X-linked IAP; XIAP) complexed with a functionally active nine-amino-acid peptide derived from the amino terminus of Smac/DIABLO. Similarly, Wu and co-workers report the high-resolution crystal structure of Smac/DIABLO in a complex with the XIAP BIR3 domain.

The BIR3 domain is a potent inhibitor for caspase-9, and wild-type Smac/DIABLO is known to interact with both the BIR2 and BIR3 domains of XIAP. The amino-terminal residues of Smac/DIABLO are needed for its function, and both papers identify the first four amino acids (Ala–Val–Pro–Ile) as being critical — they recognize a surface groove on the BIR3 domain. This recognition specificity is achieved through a series of hydrophobic interactions and van der Waals contacts between the BIR3 and Smac/DIABLO residues.

How, then, will this information aid in drug design? Some cancers overexpress IAPs, preventing apoptotic removal of the cancerous cells. Small molecules that mimic the effects of Smac/DIABLO could therefore be good potential drugs for killing these cells. And armed with the knowledge of the structure of the Smac/DIABLO-binding groove, it should be possible to design high-affinity compounds that can slot into this groove.