Goal
The long-range goal of the Protein Structure Initiative (PSI) is to make the three-dimensional atomic-level structures of most proteins easily obtainable from knowledge of their corresponding DNA sequences.
Background
With the completion of the sequencing of the genomes of human and other organisms, attention has focused on the characterization and function of proteins, the products of genes. The availability of sequence data and the growing impact of structural biology on biomedical research have prompted scientific groups from several countries to undertake projects in the emerging field of structural genomics. Plans center on a coordinated international effort to determine protein structures on a large scale. The objective is to make these structures widely available for clinical and basic studies that will expand the knowledge of the role of proteins both in normal biological processes and in disease. The National Institute of General Medical Sciences (NIGMS) played a major role in the early planning for structural genomics and in 1999 organized a national program, the Protein Structure Initiative.
Organization
The PSI is accomplishing its goal by determining unique protein structures in a high-throughput mode of operation using X-ray crystallography and NMR spectroscopy to achieve a systematic sampling of major protein families and thus create a large collection of protein structures. These experimentally determined structures will be used as templates for computational modeling of related sequence homologs to produce structural coverage of a majority of sequenced genes.
During the pilot phase, major investments in technology and methodology development at the nine PSI research centers made each step of experimental structure determination more efficient, less expensive, and more likely to succeed. Specific goals included:
- Developing methodology and technology to increase success rates and lower costs of structure determination,
- Constructing and automating the protein production and structure determination pipeline, and
- Determining unique protein structures (less than 30% identical in sequence to proteins for which structures had already been determined).
In the production phase, which began in 2005, the PSI has evolved into an interacting network. Four large-scale research centers are using the structural genomics pipeline to determine the structures of a selected fraction of proteins identified from analyses of gene sequences as targets for family representatives. The selected targets will optimize structural coverage of sequenced genes. In addition, the relationships of structures to biological function and disease will be explored. NIGMS is setting target selection policy for the PSI following discussions with advisors and the scientific community. In the future, the large-scale centers could also serve as centralized facilities capable of quickly providing structural information in response to critical biological and medical problems. Six specialized centers are focusing on technology and methodology development for high-throughput X-ray and NMR structure determination. Specific topics include protein production and crystallization of proteins that are not at present amenable to high-throughput approaches. Such proteins include membrane proteins, proteins that are in complexes, and human proteins. Two homology modeling center grants and a research project grant program are underway, focused on the improvement of computational methods of comparative modeling of protein structures. Additionally, a Materials Repository and Structural Genomics Knowledgebase have been established to provide the scientific community with access to protein expression clones and structural, functional, and experimental information generated by the PSI.
The overall goals of the production phase include:
- Providing structural coverage of sequence families, including those of known high biological importance;
- Continuing methodology and technology development, especially for challenging classes of proteins such as membrane proteins; and
- Increasing promotion of the use of structures by the broader biological community.
Benefits
As it grows, the PSI collection of structures is expected to have a significant impact on biological and medical research, in a similar way to the Human Genome Project. Expected benefits include the following:
- Structural descriptions will help researchers illuminate structure-function relationships and thus formulate better hypotheses and design better experiments.
- The PSI collection of structures will serve as the starting point for structure-based drug development by permitting faster identification of lead compounds and their optimization.
- The PSI collection of structures will assist biomedical investigators in research studies of key biophysical and biochemical problems, such as protein folding, evolution, structure prediction, and the organization of protein families and folds.
- Technical developments, the availability of reagents and materials, and experimental outcome data in protein production and crystallization will directly benefit all structural biologists and provide valuable assistance to a broad range of biomedical researchers.
