Nature Structural & Molecular Biology pp 412 - 419

Researchers have determined the structure of an enzyme that inactivates the nerve agent sarin and related toxic molecules. The results, published in the May issue of Nature Structural & Molecular Biology, provide insights into how the enzyme selects its targets and how this selectivity can be fine-tuned toward a particular set of targets.

Paraoxonase cleaves and inactivates toxic organophosphates such as sarin. It is also a component of the high-density lipoprotein particle (HDL, the 'good cholesterol') and its activity is involved in preventing the formation of fatty deposits on the artery walls. Paraoxonase is thus valuable from both antibioterrorism and medical perspectives. To understand how a single enzyme can act on such a broad spectrum of targets, Danny Tawfik and colleagues have determined the crystal structure of a mammalian paraoxonase. Structural and mutational analyses suggest the location of the active site and how the enzyme selects its targets. These results provide a basis for engineering the enzyme's activity toward a subset of its substrates for various biomedical applications.

Nature Structural & Molecular Biology pp 469 - 474

HIV is notorious for the ability to escape many drugs designed to stop its action. However, these viruses do not readily develop resistance to tenofovir, a drug that inhibits a viral protein called reverse transcriptase (RT) that is crucial for replicating the viral genome. A study in the May issue of Nature Structural & Molecular Biology reports two related structures of RT with bound tenofovir. The results explain the unusually low resistance of HIV to tenofovir.

HIV RT synthesizes a single-stranded DNA based on the viral genome RNA template. Similar to other drugs in its class, tenofovir resembles one of the four building blocks of DNA and can be incorporated into the growing DNA chain by HIV RT. After incorporation, these inhibitors stop further chain growth, therefore preventing the production of new viral genome. However, HIV resistance to tenofovir develops much slower than that to other inhibitors in this class, such as AZT.

To understand the basis for this low resistance, Eddy Arnold and colleagues have determined the structures of HIV RT bound to RNA-DNA template-primer and tenofovir. The structures show that mutations in RT that could reduce tenofovir incorporation would also substantially diminish the natural function of the enzyme. Furthermore, incorporated tenofovir can escape 'correction' activity of RT by moving out of the active site of the enzyme with the growing chain. The structures thus provide insights into the mechanisms of HIV drug resistance.