Nature Structural Biology pp 744 - 748

The central dogma says that DNA goes to RNA goes to protein. While this sounds simple enough, it is far from it. The process by which the information in the DNA is converted into RNA known as transcription is a complicated one. It involves the basic transcription machinery, which includes the RNA polymerase, and many activators and coactivators. The activators enhance transcription and the coactivators bridge the activators to the general transcription machinery. The details of how these proteins function to stimulate transcription is not clear.

Now, Tom Alber and coworkers at the University of California, Berkeley, USA have determined how one activator-coactivator pair functions to stimulate transcription. The activator they studied, hepatocyte nuclear factor-1α (HNF-1α), is an important regulator of genes in liver, kidney, stomach and pancreatic islet cells. In the test tube, when HNF-1α binds its coactivator (dimerization cofactor of HNF-1, also known as DCoH), transcription is enhanced.

Solving the three-dimensional structure of the complex by X-ray crystallography they showed that it is composed of two copies each of HNF-1α and DCoH (a 'dimer of dimers'). Previous work showed that isolated DCoH forms a tetramer (in which there are four copies of DCoH) in solution that is transcriptionally inactive. In the complex, HNF-1α binds to the same surface that typically mediates DCoH tetramer formation. Thus, formation of the inactive DCoH tetramer competes with formation of the active HNF-1α-DCoH complex. This mechanism of competition differs from more standard regulatory mechanisms in which conformationals changes alter the affinities of the proteins for one another.

Almost 100 human HNF-1α mutations have been associated with an inherited form of diabetes known as maturity-onset diabetes of the young type 3 (MODY3). The structure suggests how some of these mutations could reduce activator function. For example, mutations that inhibit the formation of the HNF-1α dimer would affect its interaction with DCoH, DNA binding and ultimately transcription. Thus, the structure of the DCoH-HNF-1α complex illustrates one way in which activators and coactivators can cooperate to stimulate transcription, and also how this process can be disrupted to cause disease.

Nature Structural Biology pp 762 - 765

Cell death is not always a bad thing. In fact it is essential to keep tumor or virally infected cells in check. Within our bodies, cytotoxic lymphocytes can kill these undesirable cells because they are armed with molecules called 'granzymes'. These processing enzymes (proteases) work by recognizing a longer form of a protein (pro-protein) and cutting off part of it. In the case of granzymes, this cleavage reaction leads to activation of a group of enzymes known as 'caspases'. Caspases comprise a family of proteases some of whose members are involved in apoptosis (programmed cell death).

While most proteases are specific for a particular protein or substrate, granzyme B has two unique requirements. Its substrate needs to be extended, that is, not highly structured and a specific amino acid (aspartic acid) must be located next to the site of cleavage. The molecular basis of this remarkable specificity is now revealed in the three-dimensional structure of granzyme B in complex with an inhibitor.

Sandra Waugh, Charles Craik and coworkers at the University of California, San Francisco, USA show that the essential aspartic acid of the substrate fits into a pocket of granzyme B where the cleavage reaction occurs. In addition, there are a number of distinct sites on the surface of the protease that make specific contacts with the substrate. Interestingly, some of these same sites can be found throughout the subfamily of serine proteases. This suggests that it may be possible to predict the specificity of a protease by looking at its amino acid sequence.

Nature Structural Biology pp 711 - 743

When the structures of biomolecules (proteins, DNA and RNA) are revealed they are typically static pictures or snap shots. But to understand how these molecules work in the cell it is important to get a sense of how they move or change shape in response to different conditions or when they interact with other molecules.

Recent developments in biophysical techniques have led to a number of new methods to study the movement of molecules. In this issue of Nature Structural Biology these techniques are highlighted in seven review articles. The reviews summarize the technical advances and point out the strengths and limitations of the techniques with an emphasis on their application to biologically relevant questions.

Since structure determination is becoming more and more routine, the next challenge facing structural biologists is to understand how and why molecules change shape. These reviews give us a taste of what is to come.