Goal
The goal of PSI:Biology is to apply the paradigm of high-throughput structure determination via highly organized networks of investigators to solve the three-dimensional structure of proteins and macromolecular complexes of substantial biological and biomedical problems and to use these structures to understand their biological function.
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 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. In 1999, the Institute organized a national program, the Protein Structure Initiative (PSI), to make protein structures widely available for clinical and basic studies and, as a result, expand knowledge of the proteins’ role in normal biological processes and in disease. Since then, PSI-supported investigators have developed new high-throughput structure determination methods and technologies that have reduced the costs and lessened the time it takes to solve a structure. In 2010, NIGMS launched a new phase of the initiative that emphasizes the use of high-throughput structure determination methods developed during the earlier PSI phases to address significant problems in biomedicine. To reflect this, the Institute renamed the effort PSI:Biology. During PSI:Biology, a highly organized network of investigators continue to develop high-throughput methods and technologies for structure determination. The majority of targets for structure determination are defined through collaborations with investigators studying function and through an open, on-going community nomination process.
Organization
PSI:Biology includes five main components:
1. Centers for High-Throughput Structure Determination
These centers determine protein structures utilizing high-throughput capabilities; continue the development of technology to improve the pipeline and to attack increasingly difficult proteins and complexes of proteins at high-throughput; carry out bioinformatics analysis of potential targets and solved structures; generate models based on solved structures; disseminate information and materials via the PSI:Biology Materials Repository and PSI:Biology Structural Biology Knowledgebase; and conduct collaborative research with other members of the PSI:Biology network.
2. Centers for Membrane Protein Structure Determination
These centers focus on the solution of membrane protein structures of high biological interest and on the development of new methods for rendering membrane protein structures more amenable to high-throughput structure determination. Within the realm of membrane protein structures, these centers have similar responsibilities to the high-throughput structure determination centers, including determining structures, developing technology, using bioinformatics analysis and modeling to leverage solved structures, disseminating information and materials and conducting collaborative research.
3. Consortia for High-Throughput-Enabled Structural Biology Partnerships
This group of investigators ensures that a broad community of scientists participates in and benefits from high-throughput structural biology. These researchers, who are not associated with the above centers, collaborate with the PSI:Biology network as a whole. Scientific problems proposed by these investigators make effective use of the high-throughput capabilities of the centers and provide a driver for further technology development. They include functional characterization of proteins and thus provide a key link between a structure and its biomedical impact. Investigators participating in these consortia abide by the PSI rules regarding identification of targets and timely distribution of materials and results.
4. The PSI:Biology Structural Biology Knowledgebase
The Knowledgebase plays an important role in information dissemination and coordination of activities across the PSI:Biology network. It provides information on targets, project progress, materials and methods, raw structure data and coordinates via the PDB, enhanced annotation of protein function, a portal to models generated from existing experimental data and additional links. It also enables the community to nominate targets for structure determination and fosters an awareness of structural genomics and structural biology across the wider scientific community.
5. The PSI:Biology Materials Repository
The Materials Repository will continue to provide centralized collection, maintenance, storage and distribution of vectors and clones generated by the PSI investigators. As more clones and structures are produced, the Materials Repository will continue to serve and enable researchers worldwide to access these valuable reagents.
PSI:Biology supports two additional components:
1. Technology Development for High-Throughput Structural Biology Research
The goal of this effort is to enhance the efficiency of structure determination, particularly for the study of membrane proteins, protein complexes, nucleic acids and protein-nucleic acid complexes, and lead to improvements in high-throughput structure determination technology.
2. Technology Development for Protein Modeling
This effort supports research methods to leverage experimentally determined structures, improve the ability to solve structures with sparse experimental constraints and make modeling more accessible and transparent to non-experts in the field.
Benefits
The PSI:Biology network of collaborative investigators continues the impressive development of large teams working in a cooperative fashion with clearly articulated goals and close management by NIGMS staff. PSI:Biology builds on and continue the past accomplishments of the PSI in terms of numbers of new structures, the number of novel folds and the technological enhancements enabling high-throughput structure determination that consequently touch the entire field of structural biology.
The PSI:Biology initiative recognizes the overwhelming importance of membrane proteins and the significantly smaller number of structures solved relative to soluble proteins. For this reason, PSI:Biology supports the membrane protein centers to achieve advances in protein structure determination methods that increase the number of membrane protein structures.
PSI:Biology actively engages the scientific community in the selection of proteins for structure determination and is increasing its outreach, accessibility and impact on biomedical research via the PSI:Biology Structural Biology Knowledgebase. Biological material resources generated by PSI investigators are shared with the scientific community through the PSI:Biology Materials Repository and through collaborations with the PSI:Biology network. With this emphasis on outreach and dissemination, PSI:Biology will increase the impact of high-throughput structure determination and provide structures to support biomedical research.