| First Author | Jonna VR | Year | 2015 |
| Journal | J Biol Chem | Volume | 290 |
| Issue | 28 | Pages | 17339-48 |
| PubMed ID | 25971975 | Mgi Jnum | J:223312 |
| Mgi Id | MGI:5648661 | Doi | 10.1074/jbc.M115.649624 |
| Citation | Jonna VR, et al. (2015) Diversity in Overall Activity Regulation of Ribonucleotide Reductase. J Biol Chem 290(28):17339-48 |
| abstractText | Ribonucleotide reductase (RNR) catalyzes the reduction of ribonucleotides to the corresponding deoxyribonucleotides, which are used as building blocks for DNA replication and repair. This process is tightly regulated via two allosteric sites, the specificity site (s-site) and the overall activity site (a-site). The a-site resides in an N-terminal ATP cone domain that binds dATP or ATP and functions as an on/off switch, whereas the composite s-site binds ATP, dATP, dTTP, or dGTP and determines which substrate to reduce. There are three classes of RNRs, and class I RNRs consist of different combinations of alpha and beta subunits. In eukaryotic and Escherichia coli class I RNRs, dATP inhibits enzyme activity through the formation of inactive alpha6 and alpha4beta4 complexes, respectively. Here we show that the Pseudomonas aeruginosa class I RNR has a duplicated ATP cone domain and represents a third mechanism of overall activity regulation. Each alpha polypeptide binds three dATP molecules, and the N-terminal ATP cone is critical for binding two of the dATPs because a truncated protein lacking this cone could only bind dATP to its s-site. ATP activates the enzyme solely by preventing dATP from binding. The dATP-induced inactive form is an alpha4 complex, which can interact with beta2 to form a non-productive alpha4beta2 complex. Other allosteric effectors induce a mixture of alpha2 and alpha4 forms, with the former being able to interact with beta2 to form active alpha2beta2 complexes. The unique features of the P. aeruginosa RNR are interesting both from evolutionary and drug discovery perspectives. |
