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Structural Biology and Computing provide robust tools to dissect mechanisms of disease.

To fully elucidate reaction mechanisms, develop effective functional probes, or rationalize searches for small molecule inhibitors, one usually needs to determine the precise position of atoms in active sites of macromolecules. In our laboratory we determine high resolution atomic structures of proteins and RNAs using X-ray crystallography. We are positioned on the interface of structural biology and computations, allowing us to deploy a variety of modern tools to study macromolecules.

Our three key areas of interest include:

• Mechanistic studies of Lin28: a microRNA biogenesis regulator, a reprogramming factor, and an oncofetal protein. We have recently determined high resolution crystal structures of Lin28 in complexes with various microRNAs. The Lin28/microRNA complex is an intriguing system that our laboratory now uses to explore general principles of protein:RNA interactions and develop small molecule probes.

• Mechanistic studies of proteins from the microRNA biogenesis pathway. Let7 microRNA precursors are processed into mature microRNAs by Dicer and DGCR8/Drosha, and this activity can be inhibited by interaction of let7s with Lin28. Lin28 can also induce degradation of let7 though the uridylase/exonuclease pathway (TUT4/Dis3l2). We are interested in the mechanism of this degradation and are pursuing structural and functional studies of macromolecular complexes involved in this pathway. This work is supplemented by computational simulations.

• Deployment of research computing “cloud” resources to accelerate structure determination. Our group has developed a global computing infrastructure that supports structure determination efforts in hundreds of structural biology laboratories (www.sbgrid.org). Some of the most computationally demanding workflows rely upon the vast resources of the Open Science Grid and access to this infrastructure contributes to our structure determination projects.

Last Update: 1/14/2014

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