The crystal structure shows the evolutionary relationship between SHMT and other alpha class PLP-dependent enzymes, as the fold is highly conserved. Many of the results of site-directed mutagenesis studies can easily be rationalised or re-interpreted in light of the structure presented here. For example, His 151 is not the catalytic base, contrary to the findings of others. A mechanism for the cleavage of serine to glycine and formaldehyde is proposed.

Aurora-2 is a key member of a closely related subgroup of serine/threonine kinases that plays important roles in the completion of essential mitotic events. Aurora-2 is oncogenic and amplified in various human cancers and could be an important therapeutic target for inhibitory molecules that would disrupt the cell cycle and block proliferation. We report the first crystal structure of Aurora-2 kinase in complex with adenosine. Analysis of residues in the active site suggests differences with structurally and biologically related protein kinases. The activation loop, which contains residues specific to the Aurora family of kinases, has a unique conformation. These results provide valuable insight into the design of selective and highly potent ATP-competitive inhibitors of the Aurora kinases.

Interleukin-2 tyrosine kinase, Itk, is an important member of the Tec family of non-receptor tyrosine kinases that play a central role in signaling through antigen receptors such as the T-cell receptor, B-cell receptor, and Fc⑀. Selective inhibition of Itk may be an important way of modulating many diseases involving heightened or inappropriate activation of the immune system. In addition to an unliganded nonphophorylated Itk catalytic kinase domain, we determined the crystal structures of the phosphorylated and nonphosphorylated kinase domain bound to staurosporine, a potent broad-spectrum kinase inhibitor. These structures are useful for the design of novel, highly potent and selective Itk inhibitors and provide insight into the influence of inhibitor binding and phosphorylation on the conformation of Itk.The Tec kinases are a family of five non-receptor tyrosine kinases that play a central role in signaling through antigenreceptors such as the T-cell receptor (TCR), 1 B-cell receptor, and Fc⑀ (1) and are essential for T-cell activation. Three members of the family, Itk, Rlk, and Tec, are activated downstream of antigen receptor engagement in T-cells and transmit signals to downstream effectors, including PLC-␥. A fourth member, Btk, appears to act independently of T-cell signaling and is essential for B-cell development and activation. Btk-deficient murine mast cells have reduced degranulation and decreased production of proinflammatory cytokines following Fc⑀RI crosslinking (2). Btk deletion in mice has a profound effect on B-cell proliferation induced by anti-IgM and inhibits immune responses to thymus-independent type II antigens (3, 4). A biological role for the final member of this family, Bmx, has not been identified.Itk is a key member of this family, and a number of factors point to the importance of this kinase in immune disease.Deletion of Itk in mice results in reduced TCR-induced proliferation and secretion of the cytokines IL-2, IL-4, IL-5, IL-10, and interferon-␥ (5-7). Also, the immunological symptoms of allergic asthma are attenuated in ItkϪ/Ϫ mice, and lung inflammation, eosinophil infiltration, and mucous production are drastically reduced in response to challenge with the allergen OVA (8). Furthermore, the Itk gene is reported to be more highly expressed in peripheral blood T-cells from patients with moderate or severe atopic dermatitis than in controls or patients with mild atopic dermatitis (9).In certain cell types, the role of Itk may be intricately linked with other members of the family. For example, in mast cells, Btk and Itk are both expressed and activated by Fc⑀RI crosslinking (10). Splenocytes from RlkϪ/Ϫ mice secrete half the IL-2 produced by wild type animals in response to TCR engagement (5), whereas the combined deletion of Itk and Rlk in mice leads to a profound inhibition of TCR-induced responses, including proliferation and production of the cytokines IL-2, IL-4, IL-5, and interferon-␥ (5, 7). Furthermore, intracellular signaling following TCR engagement is affected in Itk...

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