The Hand That Protects: Structural Insights into a Porphyrin-Binding Protein

0733 components not targeted by known kinase inhibitors. From the library of screened compounds, Shokat and colleagues identifi ed a molecule (hydroxy-PP) that, though structurally related to a known kinase inhibitor, induced morphological changes distinct from any known kinase inhibitor. What does hydroxy-PP target? An enzyme, called carbonyl reductase 1 (CBR1), that acts on xenobiotics like anticancer drugs and is thought to cause the heart damage associated with daunorubicin chemotherapy. To better understand how compound and enzyme interact, the authors solved the structure of hydroxy-PP and CBR1 bound together. Knowing their respective structures also suggests ways of enhancing a molecule’s effect on a target. In this case, Shokat and colleagues used their structural analysis to increase hydroxy-PP’s inhibition of CBR1 in cell culture so they could further explore the enzyme’s biological function. These experiments revealed a previously uncharacterized role for CBR1 in programmed cell death. Given the enzyme’s suspected role in chemotherapy-related cardiotoxicity, inhibiting CBR1 activity might enhance the effi cacy of chemotherapy treatments by reducing their debilitating side effects—a possibility that future studies can explore. But for now, Shokat and colleagues have demonstrated the power of using high-throughput image-based screening to identify small molecules both for probing cell biology and for identifying promising drug candidates.