An integrated structural biology approach to mechanism, dynamics and allosteric activity regulation in ribonucleotide reductases

We study the structural basis for mechanism, allosteric and transcriptional regulation of the family of essential enzyme family ribonucleotide reductases (RNRs), which produce the building blocks for DNA synthesis and repair in almost all organisms.

We apply multiple structural and biophysical methods including X-ray crystallography, cryo-EM, NMR and small angle X-ray scattering.RNRs are highly allosterically regulated for overall activity and substrate specificity.

A ~100-residue, evolutionarily mobile domain known as the ATP-cone regulates activity by driving the formation of a variety of oligomers of different shapes and stoichiometries.

These have in common that they sterically prevent the formation of active complexes, but the oligomers and the way they prevent active complex formation vary greatly.

We study the structure and function of RNR complexes from several organisms and different classes of RNR that operate under different physiological conditions, as well as in the ATP-cone-containing transcription factor NrdR that regulates transcription of all RNRs in bacteria.

As well as understanding the evolutionary history of the ATP cone domain, we will exploit the structural information to generate new drugs that kill human bacterial pathogens by disrupting their allosteric regulation or transcription.We also study the structural basis for radical generation in anaerobic RNRs, which is of great interest for the wider family of glycyl radical enzymes.