Biology subjects

Vedadi, M.

Publications and source records attributed to Vedadi, M..

3 recordsLinked to original sources

bioRxiv2018

MLL1 minimal catalytic complex is a dynamic conformational ensemble susceptible to pharmacological allosteric disruption

Histone H3K4 methylation is an epigenetic mark associated with actively transcribed genes. This modification is catalyzed by the mixed lineage leukaemia (MLL) family of histone methyltransferases including MLL1, MLL2, MLL3, MLL4, SET1A and SET1B. Catalytic activity of MLL proteins is dependent on interactions with additional conserved proteins but the structural basis for subunit assembly and the mechanism of regulation is not well understood. We used a hybrid methods approach to study the assembly and biochemical function of the minimally active MLL1 complex (MLL1, WDR5 and RbBP5). A combination of small angle X-ray scattering (SAXS), cross-linking mass spectrometry (XL-MS), NMR spectroscopy, and computational modeling were used to generate a dynamic ensemble model in which subunits are assembled via multiple weak interaction sites. We identified a new interaction site between the MLL1 SET domain and the WD40 repeat domain of RbBP5, and demonstrate the susceptibility of the catalytic function of the complex to disruption of individual interaction sites.

biophysics↗

bioRxiv2018

Targeting Human Retinoblastoma Binding Protein 4 (RBBP4) and 7 (RBBP7)

RBBP4 and RBBP7 (RBBP4/7) are highly homologous nuclear WD40 motif containing proteins widely implicated in various cancers and are valuable drug targets. They interact with multiple proteins within diverse complexes such as NuRD and PRC2, as well as histone H3 and H4 through two distinct binding sites. FOG-1, PHF6 and histone H3 bind to the top of the donut shape seven-bladed {beta}-propeller fold, while SUZ12, MTA1 and histone H4 bind to a pocket on the side of the WD40 repeats. Here, we briefly review these six interactions and present binding assays optimized for medium to high throughput screening. These assays enable screening of RBBP4/7 toward the discovery of novel cancer therapeutics.

biochemistry↗

bioRxiv2018

A Chemical Biology Toolbox for the Study of Protein Methyltransferases and Epigenetic Signaling

Protein methyltransferases (PMTs) comprise a major class of epigenetic regulatory enzymes with therapeutic relevance. Here we present a collection of chemical probes and associated reagents and data to elucidate the function of human and murine PMTs in cellular studies. Our collection provides inhibitors and antagonists that together modulate most of the key regulatory methylation marks on histones H3 and H4, providing an important resource for modulating cellular epigenomes. We describe a comprehensive and comparative characterization of the probe collection with respect to their potency, selectivity, and mode of inhibition. We demonstrate the utility of this collection in CD4+ T cell differentiation assays revealing the remarkable potential of individual probes to alter multiple T cell subpopulations with important implications for T cell-mediated processes such as inflammation and immuno-oncology. In particular, we demonstrate a role for DOT1L in limiting Th1 cell differentiation and maintaining lineage integrity.

biochemistry↗