Nature Structural Biology pp 19-25

Some important hormones and neuropeptides are 'chopped' by a specific enzyme, modulating their activity in vivo. This enzyme functions in the immune system, nutrition, cancer and HIV infection, and inhibiting this enzyme has been shown to lessen experimental arthritis and may offer a strategy for treating type 2 diabetes. The crystal structure of this 'chopping' enzyme, reported in the January issue of Nature Structural Biology, suggests the structural basis for this precise form of protein modulation.

Dipeptidyl peptidase IV (DPP-IV) specifically chops small proteins, including chemokines and peptide hormones involved in glucose homeostasis, after proline or alanine residues close to their amino terminus. Hanne Rasmussen and colleagues at Novo Nordisk in Denmark describe the structure of DPP-IV with a small molecule inhibitor bound. Because regulation of DPP-IV activity may have therapeutic benefits, some inhibitors are currently in clinical trials for type 2 diabetes. The structure described should provide a basis for the design of novel drugs to target this and related enzymes.

Nature Structural Biology pp 33-37

Large DNA chunks in human genes do not encode for proteins. Many considered these regions, known as introns, as 'molecular junk'. A paper in the January issue of Nature Structural Biology shows how a repeated DNA sequence within an intron can dramatically influence the processing of RNA and provide a mechanistic link to disease.

Following transcription of DNA into RNA, introns are spliced out. Complex organisms appear to use the 'splicing' process to generate combinatorial diversity. On the downside, a significant proportion of DNA mutations responsible for human disease cause aberrant splicing; thus there has been interest in identifying processes that stimulate or inhibit splicing. But few laboratories have ventured to look for these regulators in introns. Now, Bindereif and colleagues (University of Giessen, Germany) identify a human protein that recognizes a specific dinucleotide repeat sequence in an intron of the human endothelial nitric oxide synthase (eNOS) gene. By binding to these repeats, the protein enhances the removal of the intron from the transcribed RNA. The larger the number of dinucleotide repeats, the higher the splicing efficiency. Since such intronic enhancer sequences are present in disease-relevant genes, a potential link between intron sequences and disease is likely. After all, as we all know, some 'junk' may actually be quite toxic.