Nature Structural Biology pp 903 - 909

Structural genomics is touted by many to be the next big thing - one of the next important phases of genomic analysis, after sequencing of many genomes (including that of our own species) is complete.

The sequencing of the human genome 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.

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.

Later this year, the National Institute of General Medical Sciences of the National Institutes of Health in the USA plans to fund several large centers devoted to structural genomics. In the USA and Canada, several pilot projects have been underway to determine the feasibility of high-throughput structure determination. Several are attempting to answer the question: can we expect to determine the structure of every protein in an organism, even one with a small genome such as a bacterium?

Now, in the October issue of Nature Structural Biology, Cheryl Arrowsmith and Aled Edwards, of the University of Toronto, and their colleagues give us one of the first looks at the results from one of these pilot projects. They report the progress of their group in analyzing 424 nonmembrane proteins from Methanobacterium thermoautotrophicum The primary goals of their research were to evaluate the technical hurdles involved in such a high-throughput structure determination project, to estimate the percentage of proteins encoded by a genome that are immediately amenable to structural analysis, and to assess the extent to which function can be inferred from the structure of a protein.

Their work indicates that structural genomics is a technically feasible concept but also highlights that there are hurdles to be overcome. For example, they note that the rate of structure determinations for this project was limited by access to expensive instrumentation, such as NMR spectrometers and the synchrotron radiation sources that produce the intense X-ray beams needed to analyze proteins by X-ray crystallography. Therefore, they propose that this is one of the major issues that should be addressed in the pending large scale, internationally coordinated structural genomics projects.

Nature Structural Biology pp 918 - 925

The discovery of penicillin marks the beginning of the development and widespread application of antibiotics to treat bacterial infection. Penicillin and its cousins, such as cephalosporins, interfere with the synthesis of bacterial cell wall, thereby weakening the barrier that protects bacteria from the environment. These antibiotics share a common structural framework, called the β-lactam ring, which is the chemically active component of the compounds.

Antibiotics have been so effective at killing bacteria that some had declared that the war against bacterial infection has been won. However, the insurgence of antibiotic-resistant microorganisms in recent years has become a serious public health issue. One mechanism by which bacteria become resistant to the β-lactam antibiotics is to produce enzymes—β-lactamases—that destroy these compounds.

There are now more than 100 known β-lactamases that inactivate the battery of β-lactam antibiotics. One class of β-lactamases—the class D enzymes—are sometimes found encoded on circular pieces of DNA that can be transferred from one bacterial strain to another. This allows possible widespread distribution of antibiotic resistance and poses a serious health threat. Thus, effective inhibitors that stop the action of β-lactamases are desperately needed.

To allow rational design of class D β-lactamase inhibitors, Natalie Strynadka and coworkers at the University of British Columbia in Vancouver, British Columbia, Canada have determined the high resolution crystal structure of a class D enzyme. With the structures for representatives from all classes of β-lactamases now known, it is possible to plan new strategies for a counterattack against the β-lactam-resistant bacteria.

Nature Structural Biology pp 862 - 865

Ribosomal, transfer and messenger RNAs all play critical roles in protein synthesis. Transfer RNAs act as adaptor molecules since they contain the triplet anticodon code for a particular amino acid. Enzymes known as aminoacyl-tRNA synthetases attach an amino acid to the transfer RNA (tRNA) and these so-called charged tRNAs are then used to translate the genetic code from messenger RNA into protein. The three-dimensional shape of the tRNA is important for the synthetases to be able to charge the tRNA.

Changes or mutations in a number of human mitochondrial tRNA genes have been associated with a wide variety of human diseases. Mitochondria are the energy producing machines in mammalian cells and they encode a complete set of tRNAs, sufficient to support mitochondrial protein synthesis.

To understand how these changes lead to cellular dysfunctions, Paul Schimmel and coworkers at the Scripps Research Institute in La Jolla, California, USA studied mutations associated with a particular disease known as opthalmoplegia. They found that mutant tRNAs impaired the ability of the synthetase to add the amino acid. These tRNAs contained mismatched base pairs in different parts of the molecule that could be 'fixed' by replacement with a properly matched base pair. Based on these studies they suggest that the instability of the overall shape of the tRNA molecule is responsible for the disease. It will be interesting to understand in more detail how reductions in mitochondrial energy (ATP) production in nerve, muscle or other tissues contribute to various degenerative diseases.

Nature Structural Biology pp 817 - 861

While RNA's claim to fame is that it can catalyze various reactions in the absence of proteins, in the cell RNAs do so with the help of proteins. RNA-protein complexes play essential roles in virtually every aspect of cell growth and regulation, including protein transport, many forms of RNA processing, RNA editing and modification, and DNA replication. Within these complexes, RNA can act as a catalyst, it can target specific sequences or it can act as a substrate. Likewise, proteins can play structural, functional, or regulatory roles.

The seven reviews in this special issue of Nature Structural Biology summarize the current understanding of how RNAs and proteins collaborate to carry out some of these fundamental cellular processes.

The first review by Caprara and Nilsen functions as an introduction to "The wonderful world of RNA"; Williamson discusses how RNAs and proteins change shape when they interact; the question of who does what is addressed by Collins and Guthrie in the context of the messenger RNA splicing machinery and by Blackburn within the RNA-protein complex that is responsible for keeping the ends of the chromosome intact; how RNAs are capped, polyadenylated (Shatkin and Manley) and degraded (Mitchell and Tollervey) in the cell is also discussed. The last review by Puglisi, Blanchard and Green takes us on a guided tour of the awe-inspiring high-resolution structures of the large and small subunits of the ribosome, the protein-making factory found in all cells. Nobel prize winner Sidney Altman tells about how he came to study RNaseP in the History section.