Solution Structure of the KIX Domain of CBP Bound to the Transactivation Domain of c-Myb

Tsaffrir Zor, Roberto N. De Guzman, H. Jane Dyson, Peter E. Wright

Research output: Contribution to journalArticlepeer-review


The hematopoietic transcription factor c-Myb activates transcription of target genes through direct interactions with the KIX domain of the co-activator CBP. The solution structure of the KIX domain in complex with the activation domain of c-Myb reveals a helical structure very similar to that adopted by KIX in complex with the phosphorylated kinase inducible domain (pKID) of CREB. While pKID contains two helices, αA and αB, which interact with KIX, the structure of bound c-Myb reveals a single bent amphipathic helix that binds in the same hydrophobic groove as the αB helix of pKID. The affinity of c-Myb for KIX is lower than that of pKID, and relies more heavily on optimal interactions of the single helix of c-Myb with residues in the hydrophobic groove. In particular, a deep hydrophobic pocket in KIX accounts for more than half the interactions with c-Myb observed by NMR. A bend in the α-helix of c-Myb enables a critical leucine side-chain to penetrate into this pocket more deeply than the equivalent leucine residue of pKID. The components that mediate the higher affinity of pKID for KIX, i.e. the phosphate group and the αA helix, are absent from c-Myb. Results from isothermal titration calorimetry, together with the structural data, point to a key difference between the two complexes in optimal pH for binding, as a result of differential pH-dependent interactions with histidine residues of KIX. These results explain the structural and thermodynamic basis for the observed constitutive versus inducible activation properties of c-Myb and CREB.

Original languageEnglish
Pages (from-to)521-534
Number of pages14
JournalJournal of Molecular Biology
Issue number3
StatePublished - 26 Mar 2004
Externally publishedYes


  • CBP, CREB-binding protein
  • CREB-binding protein
  • Constitutive activation
  • HSQC, heteronuclear single quantum coherence
  • KID, kinase-inducible activation domain
  • LXXLL motif
  • Transcriptional activation
  • pKID, phosphorylated KID


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