Ishwar Radhakrishnan Structure, function, dynamics & informatics of eukaryotic transcription factors

Research Interests

Research in the Radhakrishnan lab focuses on the molecular mechanisms of eukaryotic transcription regulation with emphasis on how transcription factors engage with DNA, recruit specific coactivators and corepressors via intrinsically disordered transactivation or transrepression domains and how multi-protein coactivator/corepressor-bearing chromatin-modifying complexes assemble and engage with chromatin. We are asking these questions in the context of (i) nuclear receptors that use atypical mechanisms to effect transcriptional activation and (ii) a cohort of related, yet functionally distinct, histone deacetylase (HDAC)-associated chromatin-modifying complexes that fundamentally impact on cellular physiology in eukaryotes. We address these questions using molecular biological, biochemical, and biophysical approaches including solution NMR spectroscopy, electron paramagnetic resonance (EPR), macromolecular X-ray crystallography, and cryogenic electron microscopy (cryoEM) as well as computational approaches including informatics and molecular dynamics (MD) simulations. Both projects have immense biological and biomedical significance as inhibitors of HDACs and nuclear receptors are targets for treating a variety of human diseases including cancer.

Current projects in the lab focus on the NR4A family of nuclear receptors comprising Nur77, Nurr1, and NOR1. Each of these receptors plays important roles in metabolism, inflammation, and the proper development of dopaminergic neurons, among others. We are asking how these rather atypical receptors activate transcription via their ligand-binding domain as well as their activation domain at the N-terminus of these proteins. We are also asking whether these receptors function in a ligand-dependent or ligand-independent manner. Separately, we are asking how the evolutionarily-conserved, histone deacetylase (HDAC)-containing Sin3L/Rpd3L complex is assembled, what the precise molecular role(s) of the conserved subunits, which harbor domains of poorly characterized structure and function, are, including whether they regulate HDAC activity and how the complex engages chromatin and DNA-bound factors. Finally, we are developing the next iteration of a popular web application called MONSTER that can mine experimentally-determined structures for stabilizing interactions in macromolecular complexes. New enhancements include a JavaScript-based user interface, a database for storing and mining results, a stability predictor for mutants, and an automated tool for generating evolutionary conservation profiles.

Selected Publications

A Novel Mechanism of Coactivator Recruitment by the Nurr1 Nuclear Receptor. Daffern N and Radhakrishnan I. Journal of Molecular Biology. 2022 August 30;434(16):167718.

A capped Tudor domain within a core subunit of the Sin3L/Rpd3L histone deacetylase complex binds to nucleic acid G-quadruplexes. Marcum RD, Hsieh J, Giljen M, Justice E, Daffern N, Zhang Y, and Radhakrishnan I. Journal of Biological Chemistry. 2022 February;298(2):101558.

The neuronal transcription factor Myt1L interacts via a conserved motif with the PAH1 domain of Sin3 to recruit the Sin3L/Rpd3L histone deacetylase complex. Marcum RD and Radhakrishnan I. FEBS Letters. 2020 July;594(14):2322-2330.

Inositol phosphates and core subunits of the Sin3L/Rpd3L histone deacetylase (HDAC) complex up-regulate deacetylase activity. Marcum RD and Radhakrishnan I. Journal of Biological Chemistry. 2019 September 20;294(38):13928-13938.

Solution Nuclear Magnetic Resonance Studies of the Ligand-Binding Domain of an Orphan Nuclear Receptor Reveal a Dynamic Helix in the Ligand-Binding Pocket. Daffern N, Chen Z, Zhang Y, Pick L, and Radhakrishnan I. Biochemistry. 2018 April 3;57(13):1977-1986.

View all publications by Ishwar Radhakrishnan listed in the National Library of Medicine (PubMed). Current and former IBiS students in blue.