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Crystal structures and nuclear magnetic resonance studies of the Apo form of the c-MYC:MAX bHLHZip complex reveal a helical basic region in the absence of DNA

DOI: 10.1021/acs.biochem.9b00296 DOI Help

Authors: Susan Sammak (Karolinska Institutet) , Najoua Hamdani (Karolinska Institutet) , Fabrice Gorrec (MRC Laboratory of Molecular Biology) , Mark D. Allen (MRC Laboratory of Molecular Biology) , Stefan M. V. Freund (MRC Laboratory of Molecular Biology) , Mark Bycroft (MRC Laboratory of Molecular Biology) , Giovanna Zinzalla (Karolinska Institutet)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Biochemistry

State: Published (Approved)
Published: July 2019

Open Access Open Access

Abstract: 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.

Journal Keywords: Crystals; Peptides and proteins; Genetics; Crystal structure; Conformation

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: I03-Macromolecular Crystallography

Other Facilities: ESRF

Added On: 15/07/2019 11:20


Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Genetics Chemistry Structural biology Biophysics Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)