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To be or not to be (turned off)

New near atomic-level structures reveal how a protein that creates DNA’s building blocks can be switched off.

Cells often need to make more DNA, for example when they are about to divide or need to repair their genetic information. The building blocks of DNA — also called deoxyribonucleotides — are created through a series of biochemical reactions. Among the enzymes that accomplish these reactions, ribonucleotide reductases (or RNRs, for short) perform a key irreversible step.

One prominent class of RNR contains two basic units, named alpha and beta. The active form of these RNRs is made up of a pair of alpha units (α2), which associates with a pair of beta units (β2) to create an α2β2 structure. α2 captures molecules called ribonucleotides and, with the help of β2, converts them to deoxyribonucleotides that after futher processing will be used to create DNA.

As RNR produces deoxyribonucleotides, levels of DNA building blocks in the cell rise. To avoid overstocking the cell, RNR contains an ‘off switch’ that is triggered when levels of one of the DNA building blocks, dATP, is high enough to occupy a particular site on the alpha unit. Binding of dATP to this site results in three pairs of alpha units getting together to form a stable ring of six units (called α6). How the formation of this stable α6 ring actually turns off RNR was an open question.

Here, Brignole, Tsai et al. use a microscopy method called cryo-EM to reveal the three-dimensional structure of the inactive human RNR almost down to the level of individual atoms. When the alpha pairs form an α6 ring, the hole in the center of this circle is smaller than β2, keeping β2 away from α2. This inaccessibility leads to RNR being switched off.

If RNR is inactive, DNA synthesis is impaired and cells cannot divide. In turn, controlling whether or not cells proliferate is key to fighting diseases like cancer (where ‘rogue’ cells keep replicating) or bacterial infections. Certain cancer treatments already target RNR, and create the inactive α6 ring structure. In addition, in bacteria, the inactive form of RNR is different from the human one and forms an α4β4 ring, rather than an α6 ring. Understanding the structure of the human inactive RNR could help scientists to find both new anticancer and antibacterial drugs.

To find out more

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