Nature Structural Biology pp 1062 - 1001

While protein synthesis is essential for the life of a cell, so is degradation. Proteins need to be broken down to supply the building blocks, amino acids, for new protein synthesis, to remove excess proteins, damaged proteins or those that are no longer needed. One way the cell does this is with the help of a large elaborate structure known as the proteasome.

The core of the proteasome is composed of four stacked rings where the two central beta rings are flanked by two alpha rings (that is, alpha-beta-beta-alpha). The breakdown of the protein takes place within the central chamber formed by the beta rings. Access to the chamber seems to be restricted by parts of the alpha subunits (the tails) that form a gate across the opening of the chamber as well as regulatory particles at either end. A number of lines of evidence suggest that the regulatory particles somehow act to open the gate across the chamber as well as unfold the incoming protein.

The idea that the tails of the alpha subunits form the gate and so prevent access of the protein to the chamber is now confirmed by new findings provided by Michael Groll, Michael Glickman and Daniel Finley and coworkers of the Max-Planck-Institut, Germany, the Technion-Israel Institute of Technology, Israel and Harvard University, USA, respectively. Groll and coworkers showed by X-ray crystallography that removing the tail of one alpha subunit 'opened' the gate and allowed access to the chamber. Such a truncated proteasome no longer needed the regulatory particle to activate protein degradation. However, when the tail was added back as an isolated fragment, once again access to the chamber was blocked and degradation required the regulatory particle.

Given how important it is for the cell to degrade the right protein at the right time, it is not surprising that there are a number of gates or check points where proteins are either allowed or denied access. Regardless of what other mechanisms exist, physically blocking the entrance to the chamber is clearly one way the cell prevents unregulated degradation.

Cecil Pickart and Andrew VanDemark, at the Johns Hopkins University, USA, discuss the implications of these findings and those of a related paper in Nature in an associated News and Views report.

Nature Structural Biology pp 1068-1074

Newcastle disease is considered one of the most serious infectious diseases of birds, inflicting commercial and wild flocks alike. It is particularly devastating to chickens where the death rate can reach ~100%. Newcastle disease is caused by strains of a virus in the paramyxoviridae family; other members of this family cause human diseases such as mumps, as well as upper respiratory infections (for example, croup) in children. While vaccines are available to prevent infection of the Newcastle disease virus and some paramyxoviruses, there is currently no effective treatment against these pathogens after infection.

On the surface of these viruses are 'spikes' containing two proteins, one of which is called hemagglutinin-neuraminidase (HN). The spikes are the major components that elicit the immune response in the host organism; moreover, HN is essential for two steps in the viral infection cycle: host cell targeting and viral maturation. In the early step of infection, the HN protein targets the virus particle to the host cell: HN binds to a compound called sialic acid on the cell surface. In the maturation step, the newly formed virus buds from the host cell, and sialic acid compounds on the surface of the emerging viruses are removed by the HN protein, to prevent self-attachment of the virus particles. Inhibiting either function of HN disrupts the viral infection cycle. Thus, the HN protein is potentially a good target for developing treatments against this family of viruses.

To understand how the HN protein performs its functions, Garry Taylor of the University of St. Andrews, UK, and coworkers have determined the X-ray crystal structures of the catalytic domain of HN from the Newcastle disease virus in complex with either an enzyme inhibitor or a compound that resembles the substrate. These structures support a surprising hypothesis - that a single active site is utilized for both functions of the HN protein. In other words, both the stable binding of HN to sialic acid on the host cell surface during the targeting step and the removal (cleavage) of sialic acid from the viral surface during the maturation step appear to occur in the same place on the HN protein. Switching between these two functions is apparently regulated by conformational changes within the protein. These structures provide a foundation for structure-based drug design against the paramyxoviruses.

Nature Structural Biology pp 927 - 994

This month we are presenting a special supplement to the journal, and the topic is the emerging field of Structural Genomics. This area of research represents one of the next important phases of genomic analysis, after the sequencing of many genomes (including the human genome) is complete. In this special supplement, we present a set of ~18 reviews that define the field, explain the current activities that are ongoing around the world, describe the technical hurdles that must be overcome, and cover the long-term goals and strategies of the research groups.

The sequencing of numerous genomes is important and impressive, but it will not be sufficient for the development of effective disease therapies because genes are the storehouses of genetic information in cells, not the active participants in cellular processes. Genes encode the blueprints for making proteins, which are the molecules that perform most of the functions in living organisms. Therefore, it is important to determine the function of each protein in an organism, and how it goes about performing its assigned tasks. And, to understand a protein's role in detail, it is necessary to know its structure at atomic resolution. Researchers in the field of Structural Genomics want to make it possible to obtain some atomic resolution structural information about nearly every protein.

A major goal of the field of Structural Genomics is to make the process of protein structure determination automated and extremely rapid (from ~1 year per structure currently to ~1 month or less, for example), so that we can begin to amass atomic resolution structures of all proteins. Another goal is to decrease the cost of each structure determination (from ~$200,000 currently to hopefully ~$20,000) so that the enterprise is financially feasible.

Last month (in the October issue), Nature Structural Biology published a paper that investigated the technical feasibility of Structural Genomics (Nature Struct. Biol. 7, 903-909 (2000)). This paper showed that high throughput structure determination starting only with genomic sequence information is possible with both NMR spectroscopy and X-ray crystallography, the two major techniques used for determining the atomic resolution structures of biomolecules.

In addition, in late September, the National Institute of General Medical Sciences of the National Institutes of Health in the USA funded seven large centers devoted to Structural Genomics, giving ~$4 million to each center for the first of five years.

Our supplement on Structural Genomics comes at a crucial time and should help readers understand what this field is all about.