Q. What is the Protein Structure Initiative (PSI)?
A. The Protein Structure Initiative (PSI) is a national research program in the emerging field of structural genomics. The PSI is a large-scale, high-throughput effort to increase the number of structures of unique, non-redundant proteins, permitting the study of a broad range of protein structures. This will be accomplished by a coordinated effort of federal, university, and industrial scientists to reduce costs, increase efficiency and success rates, and decrease the time for the production and determination of the three-dimensional atomic-level structures of proteins. (See: “
From Genes to Proteins: NIGMS Catalogs the Shapes of Life,”
NIH Record, February 2001.)
Q. Why was the PSI started?
A. With the sequencing of the genomes of humans and other organisms now completed, researchers are focusing their attention 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 has prompted scientific groups from several countries to undertake projects in the emerging field of structural genomics. The National Institute of General Medical Sciences (NIGMS) played a major role in the early planning for structural genomics projects. In 1999, after extensive consultation with leading experts in the field, NIGMS launched a national program, the Protein Structure Initiative (PSI).
Q. What is the goal of structural genomics?
A. Plans center on a coordinated, international effort to determine unique protein structures, with both known and unknown functions, on a large scale. The objective is to make these structures widely available for clinical and basic studies that will expand knowledge of the role of proteins both in normal biological processes and in disease. Structural genomics will accomplish its goal by determining unique protein structures in a high-throughput mode of operation. X-ray crystallography and NMR spectroscopy are among the key technologies used 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 developing computer models of related sequence proteins (homologs) to produce structures of a majority of sequenced genes and representative of many protein families.
Q. What is the goal of the PSI?
Q. How will the PSI accomplish that goal?
A. The first stage of the PSI began in 2000 with the creation of research centers to serve as pilots for the design of a future production phase. In addition, a research grant program focuses on methodology and technology developments in this field.
Q. What are the expected benefits of the PSI?
A. 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 design of better therapeutics will result from comparisons of the structures of proteins that are from pathogenic and host organisms and from normal and diseased human tissues.
- 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.
Q. What have the PSI centers done since the initiative started? How many structures have been discovered so far?
A. 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 through the establishment of a large-scale pipeline that included all tasks of protein structure determination. During the current production phase, which began in 2005, large-scale centers are using the structural genomics pipeline to determine the structures of a selected fraction of proteins identified from analyses of gene sequences as representative targets for protein families. The selected targets will optimize structural coverage of sequenced genes. In addition, the relationships of structures to biological function and disease will be explored. Smaller specialized centers focus 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 amenable to high-throughput approaches, such as membrane proteins and human proteins. In 2006, the PSI established two molecular modeling centers and a materials repository. In 2008, the PSI launched the Structural Genomics Knowledgebase to make all the products generated by the PSI centers available to the greater scientific community. The PSI centers have determined nearly 2900 protein structures (as of February 2008).
Q. What will be the research priorities of the PSI, and how will they be set?
A. NIGMS will set target selection policy for the large-scale PSI centers following discussions with advisors and the scientific community. These centers will also serve as centralized facilities capable of providing structural information quickly in response to critical biological and medical problems.
Q. What is the proposed budget for the PSI?
A. Total support for the nine PSI centers in the pilot phase of the project was $30 million in the first year (FY 2000), $40 million in the second year (FY 2001), $53 million in the third year (FY 2002), and $71 million in the fourth and fifth years (FY 2003-04). Total support for the PSI centers in the production phase was $66 million in the first year (FY 2005). Current funding for the PSI comes from NIGMS and NCRR, the National Center for Research Resources.
Q. How does NIGMS incorporate expert advice into management of the PSI, and what review process is in place for evaluating future applications?
A. The
Protein Structure Initiative Advisory Committee (PSIAC) has been appointed in order to assist in managing, evaluating, and planning for the PSI. The PSIAC is a working group of the National Advisory General Medical Sciences Council, the advisory body to NIGMS. The nine members of the PSIAC are prominent scientists who represent a range of scientific fields. Applications for the PSI production phase will undergo peer review and scrutiny by the National Advisory General Medical Sciences Council.
Q. How is NIGMS supporting research into the functions of proteins?
A. Functionally motivated structural studies have made major contributions to biology and medicine, and studies of this type remain a top priority at NIGMS. Of the structural biology projects that NIGMS funds, an increasing portion involve functional studies of proteins and other macromolecules. Although the PSI focuses on structural determination and funds are not provided in the PSI research center grants for functional studies, NIGMS does provide
supplements to research project (R01) grantees to pursue functional studies of interesting structures discovered by the PSI. PSI staff and advisors are considering other ways to make all the information generated by the PSI centers of maximal use to the scientific community.
Q. How does the PSI fit in with international efforts, such as the Protein Data Bank and the International Structural Genomics Organization?
A. Just as the field of structural genomics has attracted researchers worldwide, the PSI also has significant international involvement. The PSI centers themselves include many collaborating organizations from the United States, the European Union, Japan, China, Canada, and Israel. In addition, the PSI is actively working with
Protein Data Bank (PDB), the worldwide repository of 3-D biological macromolecular structure data. Under the sponsorship of NIGMS, the PDB has created a centralized registration database for target sequences from structural genomics projects worldwide at
http://targetdb.pdb.org/. The PSI is also a member of the
International Structural Genomics Organization (ISGO), which held its international conference in Beijing, China, in October 2006.
