Small-molecule perturbation of competing interactions between c-Myc and Max

https://doi.org/10.1016/j.bmcl.2008.12.025Get rights and content

Abstract

The oncogenic transcription factor c-Myc undergoes coupled binding and folding of its basic-helix-loop-helix-leucine zipper domain (bHLHZip) upon heterodimerization with its partner protein Max. The latter exists in two isoforms: p21, which homodimerizes poorly, and p22, which homodimerizes well. We show that the effect of 10058-F4 (a small-molecule that binds disordered c-Myc monomers and disrupts the c-Myc–Max complex) on both c-Myc–Max heterodimerization and DNA binding is dependent on the nature of the Max isoform. In the presence of p22 Max the effective inhibitor concentration is lower than in the presence of p21 Max, as the p22 Max homodimer formation affects the thermodynamics by competing against the c-Myc–Max heterodimerization event.

References and notes (30)

  • L.M. Iakoucheva et al.

    J. Mol. Biol.

    (2002)
  • H.J. Dyson et al.

    Curr. Opin. Struct. Biol.

    (2002)
  • P. Tompa et al.

    Trends Biochem. Sci.

    (2005)
  • E.M. Blackwood et al.

    Curr. Opin. Genet. Dev.

    (1992)
  • R. Ponzielli et al.

    Eur. J. Cancer

    (2005)
  • H. Zhang et al.

    J. Biol. Chem.

    (1997)
  • P. Brownlie et al.

    Structure

    (1997)
  • D.G. Edmondson et al.

    J. Biol. Chem.

    (1993)
  • Y. Xu et al.

    Bioorg. Med. Chem.

    (2006)
  • A. Kiessling et al.

    Chem. Biol.

    (2006)
  • S.K. Nair et al.

    Cell

    (2003)
  • H.J. Dyson et al.

    Nat. Rev. Mol. Cell Biol.

    (2005)
  • P. Romero et al.

    Appl. Bioinformatics

    (2004)
  • A.K. Dunker et al.

    Gen. Inform.

    (2000)
  • C.V. Dang

    Mol. Cell. Biol.

    (1999)
  • Cited by (0)

    View full text