In contrast to the optimal linchpin, which is conserved as arginine in half of RING-type Ub ligases55 and mutated in human cancers (Fig. 6 and Supplementary Data 3)60,61, the suboptimal linchpin is insufficient as a hydrogen bonding donor to stimulate flexible UBE2D~Ub or UBE2N~Ub intermediates into the closed conformation for robust Ub transfer56,62. This evidence concerns the gene UBE2N and cancer.