Conformational disorder in regulation of enzymatic catalysis

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Enzymes are remarkable nanomachines that play a myriad of essential functions in cellular metabolism.

Modulation of enzyme structure and flexibility by cofactor/substrate binding provides an important source of regulation of enzyme function, yet our understanding of the fundamental mechanisms coupling protein dynamics to enzymatic activity is still largely incomplete.

In the Venditti lab we use NMR combined with other biophysical and biochemical approaches to reveal how the complex interplay between cofactor/substrate binding and conformational dynamics regulates the activity of high molecular weight enzymes that are essential for human and bacterial metabolism. The systems of interest in our research are Enzyme I (EI) of the bacterial phosphotransferase system (PTS), and the human RNA demethylases FTO and Alkbh5.

Our results demonstrate a role for conformational disorder in regulating the activity of these important enzymes and suggest strategies for their selective inhibition.