The Crystal Structure of the IκBα/NF-κB Complex Reveals Mechanisms of NF-κB Inactivation

main of approximately 100 amino acids in length. All IkBa regulates the transcription factor NF-kB through dimerization contacts are mediated through this second the formation of stable IkBa/NF-kB complexes. Prior domain, referred to as the dimerization domain. The to induction, IkBa retains NF-kB in the cytoplasm until carboxy-terminal 13 amino acids (NLS polypeptide), the the NF-kB activation signal is received. After activafinal four of which contain a basic nuclear localization tion, NF-kB is removed from gene promoters through sequence (NLS), are disordered in the crystal structures, association with nuclear IkBa, restoring the preinducsuggesting flexibility. DNA base-specific contacts are tion state. The 2.3 Å crystal structure of IkBa in commade by loops emanating from the amino-terminal doplex with the NF-kB p50/p65 heterodimer reveals main, while nonspecific DNA ribo-phosphate backbone mechanisms of these inhibitory activities. The presinteractions involve loop residues from both the aminoence of IkBa allows large en bloc movement of the terminal and dimerization domains. NF-kB p65 subunit amino-terminal domain. This conIn its resting state, the p50/p65 heterodimer exists in formational change induces allosteric inhibition of NFa stable cytosolic complex with a member of the inhibitor kB DNA binding. Amino acid residues immediately prekB (IkB) family (Figure 1a) of transcription factor inhibiceding the nuclear localization signals of both NF-kB tor proteins (for reviews, Baeuerle and Baltimore, 1988; p50 and p65 subunits are tethered to the IkBa aminoVerma et al., 1995; Baeuerle and Baltimore, 1996; Baldterminal ankyrin repeats, impeding NF-kB from nuwin, 1996). Inducers of NF-kB, including bacterial and clear import machinery recognition. viral products, inflammatory cytokines, reactive oxygen,