Ribonucleotide reductases (RNRs) use radical cofactors to catalyze the reduction of ribonucleotides to deoxyribonucleotides, an essential reaction for DNA replication and repair in all organisms. RNR's crucial role in the biosynthesis of deoxyribonucleotides has made the human enzyme an attractive target for anticancer treatments with multiple FDA-approved RNR inhibitors in clinical use. Current FDA-approved drugs include the phosphorylated forms of antileukemic nucleoside analogs – cladribine (ClATP), fludarabine (FlUTP), and clofarabine (ClFTP). These nucleoside analogs have been shown to cause the catalytic alpha subunit to hexamerize; an oligomeric state change that prevents the radical-containing beta subunit from assuming a catalytic position. Importantly, for catalysis to occur, the beta subunit must associate with the alpha subunit, forming an a2b2 state that is capable of proton-coupled electron transfer (PCET). However, when too many deoxyribonucleotides are produced, RNR is turned-off by the binding of dATP to an allosteric activity site, causing a-hexamerization and thus inactivation. Here, we use cryo-electron microscopy to determine the structure of human RNR bound to ClATP to determine if the previously observed a-hexamerization is due to ClATP binding in the dATP allosteric activity site. We also investigate the possibility that phosphorylated forms of ClATP could inhibit RNR by binding to the active site and/or the allosteric specificity site that modulates the substrate preference.