NrdR-a unique nucleotide-sensing regulator of prokaryotic ribonucleotide reductases

SUMMARYThe transcriptional regulator NrdR is present in most bacteria and in some archaea, but is lacking in eukaryotes. It controls the expression of operons of the universal and essential ribonucleotide reductase (RNR) enzymes, which provide building blocks of DNA by reducing ribonucleotides to their corresponding deoxyribonucleotides. The NrdR protein consists of an N-terminal zinc-ribbon domain that can bind to specific NrdR boxes in DNA, followed by an ATP-cone domain that binds adenosine nucleotides. Discovered 20 years ago, it was not until the recent high-resolution structures of NrdR in its DNA-bound and -unbound forms that its intricate mechanism of action could be described in detail. Contrary to early assumptions, the ATP-cone in NrdR has two nucleotide-binding sites, an inner and an outer site. When cellular dATP is low, NrdR is loaded with ATP in both sites and forms oligomers unable to bind to DNA, allowing transcription of RNR-encoding operons, and DNA replication and repair. When dATP levels increase, ATP in the outer site is substituted for dATP, NrdR will bind to DNA, and the expression of RNR-encoding genes will be inhibited. Interestingly, many RNRs also carry an ATP-cone that binds either one or two adenosine nucleotides, and that acts as an allosteric on/off switch of its enzyme activity. On the basis of current knowledge, this is a unique utilization of the same horizontally transferable domain for controlling both enzyme expression and enzyme activity.