F-?B activation, IKK, especially IKK, has become a potential therapeutic target for many human diseases. The regulatory protein NEMO (also known as IKK? or FIP-3) interacts with IKKa and/or IKK to form the IKKa, IKK or IKKa/ holo-complex. The intact IKK holo-complex is approximately 700-900kD in molecular mass containing multiple copies of IKK2 and NEMO. IKKa and IKK both contain the following conserved recognizable domains: a kinase domain (KD), a leucine zipper domain (LZ), a helix loop helix domain (HLH) and a C-terminal NEMO-binding domain (NBD). NEMO contains an N-terminal kinase-binding domain (KBD), a minimal oligomerization domain (MOD) that is also the ubiquitin binding domain (UBD) and a C-terminal zinc finger domain (ZF). IKK and NF-?B signaling has attracted tremendous attention with more than 30,000 papers published on the subject. Despite the biological importance, not a single successful structure determination has been reported on IKK, an indication on the difficulty of the project. To elucidate the molecular basis of IKK function and to assist the discovery of IKK inhibitors, we propose a series of structural and functional studies on IKK, in particular, IKK and its regulatory protein NEMO. Public Health Relevance: The I?B kinase (IKK) is at the heart of NF-?B activation and a potential therapeutic target for many human diseases. The proposal seeks structural studies of IKK, which will enhance our understanding on the molecular basis of IKK function. In addition, the proposed studies will provide a structural basis for discovery and optimization of IKK inhibitors in the treatment of inflammatory diseases and cancer.

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