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 an emphasis on how transcription factors select and assemble on DNA targets, how they recruit coregulator complexes with chromatin-modifying activities, and how the latter complexes are themselves assembled and regulated.  We are asking these questions in the context of (i) so-called orphan or ligand-independent nuclear receptors that promote normal development in organisms as diverse as fly and human, (ii) a cohort of related, yet functionally distinct, histone deacetylase-associated chromatin-modifying complexes that fundamentally impact on cellular physiology in all eukaryotes, and (iii) cyclic AMP signaling mediated by the prototypical and signal-inducible factor CREB and its coactivators.  We use a broad range of biochemical, biophysical and computational approaches including solution NMR spectroscopy, x-ray crystallography, electron microscopy and molecular dynamics simulations to answer these questions.

Current projects in the lab focus on the structure, molecular evolution and dynamics (aka internal motions) of the Ftz-F1/NR5A sub-family of nuclear receptors.  We are asking how the Ftz-F1 factor in Drosophila cooperates with the homeotic protein Ftz to specifically and synergistically bind DNA and how the ligand-binding domain of Ftz-F1 has evolved to activate transcription via ligand-dependent (in mouse and human) and ligand-independent (in fly) mechanisms and the role of internal motions in dictating protein allostery by facilitating communication between the ligand-binding pocket and the coactivator-binding site.  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

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 May 11:epub before print.

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.

Molecular Basis for the Mechanism of Constitutive CBP/p300 Coactivator Recruitment by CRTC1-MAML2 and Its Implications in cAMP Signaling. Clark MD, Kumar GS, Marcum R, Luo Q, Zhang Y, and Radhakrishnan I. Biochemistry. 2015 September 8;54(35):5439-5446.

Structural insights into the assembly of the histone deacetylase-associated Sin3L/Rpd3L corepressor complex. Clark MD, Marcum R, Graveline R, Chan CW, Xie T, Chen Z, Ding Y, Zhang Y, Mondragón A, David G, and Radhakrishnan I. PNAS. 2015 July 14;112(28):E3669-E3678.

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