The c-MYC transcription
factor is a master regulator of cell growth
and proliferation and is an established target for cancer therapy.
This basic helix–loop–helix Zip protein forms a heterodimer
with its obligatory partner MAX, which binds to DNA via the basic
region. Considerable research efforts are focused on targeting the
heterodimerization interface and the interaction of the complex with
DNA. The only available crystal structure is that of a c-MYC:MAX complex
artificially tethered by an engineered disulfide linker and prebound
to DNA. We have carried out a detailed structural analysis of the
apo form of the c-MYC:MAX complex, with no artificial linker, both
in solution using nuclear magnetic resonance (NMR) spectroscopy and
by X-ray crystallography. We have obtained crystal structures in three
different crystal forms, with resolutions between 1.35 and 2.2 Å,
that show extensive helical structure in the basic region. Determination
of the α-helical propensity using NMR chemical shift analysis
shows that the basic region of c-MYC and, to a lesser extent, that
of MAX populate helical conformations. We have also assigned the NMR
spectra of the c-MYC basic helix–loop–helix Zip motif
in the absence of MAX and showed that the basic region has an intrinsic
helical propensity even in the absence of its dimerization partner.
The presence of helical structure in the basic regions in the absence
of DNA suggests that the molecular recognition occurs via a conformational
selection rather than an induced fit. Our work provides both insight
into the mechanism of DNA binding and structural information to aid
in the development of MYC inhibitors.
c-MYC and the SWI/SNF chromatin remodeling complex act as master regulators of transcription, and play a key role in human cancer. Although they are known to interact, the molecular details of their interaction are lacking. We have determined the structure of the RPT1 region of the INI1/hSNF5/BAF47/SMARCB1 subunit of the SWI/SNF complex that acts as a c-MYC-binding domain, and have localized the interaction regions on both INI1 and on the c-MYC:MAX heterodimer. c-MYC interacts with a highly conserved groove on INI1, while INI1 binds to the c-MYC helix-loop-helix region. The binding site overlaps with the c-MYC DNA-binding region, and we show that binding of INI1 and E-box DNA to c-MYC:MAX are mutually exclusive.
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