Nicolas Daffern

Nic is a 2nd year IBiS student in the Radhakrishnan lab. He received a BS in Biochemistry from Oklahoma State University. Nic can be contacted via email here.


Experimental and computational analyses of protein dynamics in the ligand-binding domain of NR5A nuclear receptors

Nuclear receptors constitute an important family of transcription factors that regulate a wide variety of fundamental processes in metazoans. Most receptors harbor two key domains, one of which binds to signaling molecules, while the other binds DNA to directly regulate transcription. Understanding the mechanisms by which nuclear receptors function is important because of their key role in developmental biology and their implications in human health and disease. The mechanisms underlying the functions of the ligand-binding domain (LBD) represents a particularly intriguing puzzle as this domain often has multiple interaction partners and is thought to undergo significant conformational changes while performing its regulatory role.

In order to elucidate these mechanisms, I will be studying an orphan receptor known as FTZ-F1 which, over the course of evolutionary history, has appeared to replace its natural ligand with one of its own alpha-helices. Bona fide orphan receptors are nuclear receptors that have no known ligand and are extremely useful for studies of LBD conformation, dynamics, function and evolution. First I will use NMR to compare the dynamics of FTZ-F1 LBD with those of other orphan or ligand-dependent nuclear receptors in the same sub-family in the presence and absence of ligands. I will then use bioinformatic approaches to reconstruct the evolutionary history of FTZ-F1, predict the function of key residues, and perform mutagenesis to manipulate the structure, function and dynamics of FTZ-F1 LBD. Finally, I will perform molecular dynamics simulations to study allosteric motions within the LBD, and in parallel, measure side chain dynamics via spin relaxation NMR experiments to correlate theory with experiment.


Recent Photos

September 29, 2016