Quaternary Structure and Activity Modulation in Human Ribonucleotide Reductase

Ribonucleotide reductase (RNR) catalyzes the conversion of nucleotides to 2´-deoxynucleotides, providing the monomeric precursors necessary for DNA replication and repair. Precise regulation of RNR activity is essential for fidelity of DNA replication, as RNR is responsible for maintaining both the correct absolute cellular concentration of deoxynucleotides, as well as the appropriate relative concentration ratios. The class Ia RNRs found in many aerobic bacteria and all eukaryotes consist of 2 protein subunits. The larger subunit α houses the active site where nucleoside diphosphate substrates (CDP, ADP, GDP, UDP) are reduced, and two additional sites for allosteric effector (ATP, dGTP, TTP, and dATP) binding. The specificity site dictates which substrate is reduced, while the activity site binds ATP/dATP and regulates the overall reduction rate. Nucleotide reduction depends on precise interaction of α with a dimeric smaller subunit β2 that contains a diferric-tyrosyl radical cofactor essential for catal...