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Instruments / Technical Area	Publication Details	Published
I03-Macromolecular Crystallography	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 Susan Sammak , Najoua Hamdani , Fabrice Gorrec , Mark D. Allen , Stefan M. V. Freund , Mark Bycroft , Giovanna Zinzalla Biochemistry DOI: 10.1021/acs.biochem.9b00296 Open Access Show Abstract ▼ 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.	Jul 2019
I03-Macromolecular Crystallography	SWI/SNF subunit BAF155 N-terminus structure informs the impact of cancer-associated mutations and reveals a potential drug binding site Mark D. Allen , Stefan M. V. Freund , Mark Bycroft , Giovanna Zinzalla Communications Biology 4 DOI: 10.1038/s42003-021-02050-z Open Access Show Abstract ▼ Abstract: SWI/SNF (BAF) chromatin remodelling complexes are key regulators of gene expression programs, and attractive drug targets for cancer therapies. Here we show that the N-terminus of the BAF155/SMARCC1 subunit contains a putative DNA-binding MarR-like domain, a chromodomain and a BRCT domain that are interconnected to each other to form a distinct module. In this structure the chromodomain makes interdomain interactions and has lost its canonical function to bind to methylated lysines. The structure provides new insights into the missense mutations that target this module in cancer. This study also reveals two adjacent, highly-conserved pockets in a cleft between the domains that form a potential binding site, which can be targeted with small molecules, offering a new strategy to target SWI/SNF complexes.	May 2021
I03-Macromolecular Crystallography	Structural basis for Pan3 binding to Pan2 and its function in mRNA recruitment and deadenylation J. Wolf , Eugene Valkov , Mark Allen , Birthe Meineke , Y. Gordiyenko , S. H. Mclaughlin , T. M. Olsen , C. V. Robinson , M. Bycroft , M. Stewart , L. A. Passmore The Embo Journal 33 (14), 1514 - 1526 DOI: 10.15252/embj.201488373 PMID: 24872509 Diamond Proposal Number(s): [8547] Open Access Show Abstract ▼ Abstract: The conserved eukaryotic Pan2–Pan3 deadenylation complex shortens cytoplasmic mRNA 3′ polyA tails to regulate mRNA stability. Although the exonuclease activity resides in Pan2, efficient deadenylation requires Pan3. The mechanistic role of Pan3 is unclear. Here, we show that Pan3 binds RNA directly both through its pseudokinase/C-terminal domain and via an N-terminal zinc finger that binds polyA RNA specifically. In contrast, isolated Pan2 is unable to bind RNA. Pan3 binds to the region of Pan2 that links its N-terminal WD40 domain to the C-terminal part that contains the exonuclease, with a 2:1 stoichiometry. The crystal structure of the Pan2 linker region bound to a Pan3 homodimer shows how the unusual structural asymmetry of the Pan3 dimer is used to form an extensive high-affinity interaction. This binding allows Pan3 to supply Pan2 with substrate polyA RNA, facilitating efficient mRNA deadenylation by the intact Pan2–Pan3 complex.	Jul 2014
I02-Macromolecular Crystallography	The structure of the FYR domain of transforming growth factor beta regulator 1 Maria Garcia-Alai , Mark D. Allen , Andreas C. Joerger , Mark Bycroft Protein Science 19 (7), 1432-1438 DOI: 10.1002/pro.404 PMID: 20506279 Open Access Show Abstract ▼ Abstract: Many chromatin-associated proteins contain two sequence motifs rich in phenylalanine/tyrosine residues of unknown function. These so-called FYRN and FYRC motifs are also found in transforming growth factor beta regulator 1 (TBRG1)/nuclear interactor of ARF and MDM2 (NIAM), a growth inhibitory protein that also plays a role in maintaining chromosomal stability. We have solved the structure of a fragment of TBRG1, which encompasses both of these motifs. The FYRN and FYRC regions each form part of a single folded module (the FYR domain), which adopts a novel α + β fold. Proteins such as the histone H3K4 methyltransferases trithorax and mixed lineage leukemia (MLL), in which the FYRN and FYRC regions are separated by hundreds of amino acids, are expected to contain FYR domains with a large insertion between two of the strands of the β-sheet.	Apr 2010

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