Fibroblast activation protein ␣ (FAP␣) is highly expressed in epithelial cancers and has been implicated in extracellular matrix remodeling, tumor growth, and metastasis. We present the first high resolution structure for the apoenzyme as well as kinetic data toward small dipeptide substrates.

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HIV/AIDS continues to be a menace to public health. Several drugs currently on the market have successfully improved the ability to manage the viral burden in infected patients. However, new drugs are needed to combat the rapid emergence of mutated forms of the virus that are resistant to existing therapies. Currently, approved drugs target three of the four major enzyme activities encoded by the virus that are critical to the HIV life cycle. Although a number of inhibitors of HIV RNase H activity have been reported, few inhibit by directly engaging the RNase H active site. Here, we describe structures of naphthyridinone-containing inhibitors bound to the RNase H active site. This class of compounds binds to the active site via two metal ions that are coordinated by catalytic site residues, D443, E478, D498, and D549. The directionality of the naphthyridinone pharmacophore is restricted by the ordering of D549 and H539 in the RNase H domain. In addition, one of the naphthyridinone-based compounds was found to bind at a second site close to the polymerase active site and non-nucleoside/nucleotide inhibitor sites in a metal-independent manner. Further characterization, using fluorescence-based thermal denaturation and a crystal structure of the isolated RNase H domain reveals that this compound can also bind the RNase H site and retains the metal-dependent binding mode of this class of molecules. These structures provide a means for structurally guided design of novel RNase H inhibitors.

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The three-dimensional structure of toxic shock syndrome toxin 1 (TSST-1) from Staphylococcus aureus has been determined and refined to an R value of 0.226 for data between 8- and 2.5-A resolution. Overall, the structure of TSST-1 is similar to that of another superantigen, staphylococcal enterotoxin B (SEB). The key differences between these molecules are in the amino termini and in the degree to which a long central helix is covered by surface loops. The region around the carboxyl end of this central helix is proposed to govern the superantigenic properties of TSST-1. An adjacent region along this helix is proposed to be critical in the ability of TSST-1 to induce toxic shock syndrome.