Small-molecule perturbation of competing interactions between c-Myc and Max.
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.
Follis
Ariele Viacava
AV
Department of Chemistry, Georgetown University, 37th & O Streets, NW, Reiss Science Center, Washington, DC 20057, USA.
Hammoudeh
Dalia I
DI
Daab
Andrew T
AT
Metallo
Steven J
SJ
D050976:Basic-Leucine Zipper Transcription Factors / Q000737:chemistry*; D001665:Binding Sites; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004247:DNA / Q000737:chemistry; D019281:Dimerization; D015195:Drug Design; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D011485:Protein Binding / Q000187:drug effects*; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D016271:Proto-Oncogene Proteins c-myc / Q000737:chemistry*; D013816:Thermodynamics
D050976:Basic-Leucine Zipper Transcription Factors; C067850:Myc associated factor X; D020033:Protein Isoforms; D016271:Proto-Oncogene Proteins c-myc; D004247:DNA