Joint Meeting of the Research Center PIs and the PSI Advisory Council (PSIAC)

October 28-29, 2004

The Protein Structure Initiative Advisory Council (PSIAC) met with the Principal Investigators of the PSI research centers, together with a number of other individuals to review progress on the NIGMS Protein Structure Initiative.

PSI-Related Activities

Prior to the reports from the individual centers, a number of issues related to the PSI initiative were discussed.

Helen Berman and Paul Adams discussed ways in which the Protein Data Bank (PDB) is being adapted to better meet the needs of the PSI initiative. There are now over 800 PSI structures in the PDB and these are now specifically annotated as PSI-derived. In order to make the structural information more relevant and more accessible, a major effort is being made to improve cross-referencing of these structures. The objective is that structures can be accessed, e.g. via their disease relevance or by the ligands they bind. The data base Target DB lists targets and progress toward structures for PSI centers and several other projects. With support from the PSI, a pilot effort to archive and make accessible information on protein expression, purification and crystallization as well as related protocols has been undertaken. It is very encouraging that Dr. Berman and her group have been so responsive to addressing the needs of the PSI.

Dr. Jerry Li (NIH) discussed progress toward a PSI knowledge base. In order to increase the value of structures determined through the PSI it is essential that improved methods be developed to predict the structures of related members of a given family.

Dr. Rick Morimoto, representing the NIH Council, discussed some of the issues involved in trying to balance the need for large-scale grants relative to individual RO1 awards.

Progress of the Individual PSI Centers

The PIs of each of the nine research centers gave short summaries of the progress that they have made. Altogether, this was both gratifying and highly encouraging. A number of the centers have developed highly efficient protocols to efficiently screen a large number of potential targets and, where possible, to proceed rapidly to structure determination. Some of the groups are currently depositing in the neighborhood of 10 structures per month in the PDB. Progress on structure determination has been impressive.* Different groups described simplifications and improvements that have been made in cloning and protein purification, as well as in “salvaging” proteins that might previously have been discarded as being intractable to eventual structure determination.

*From the statistics compiled by John Norvell the number of structures determined by all the PSI centers in years one through four of the initiative are, respectively, 77, 109, 217 and 348 for a total of 751 structures. Over the same period the estimated cost per structure has decreased in the sequence $670K, $400K, $250K and $180K. Of the structures currently being contributed by the PSI to the Protein Data Bank 72% are “unique” in the sense that they have less than 30% sequence identity with any known structure. For structures contributed to the PDB by the community at large, only 13% are “unique”. In 2003 the PSI structures constituted 42% of the total unique structures deposited into the PDB.

Overview from the PSIAC

The second day of the meeting was a closed session during which the members of the PSIAC reviewed the material that had been presented and discussed future needs. As noted in last year’s report, members of the PSIAC were highly impressed with the progress reported at that time. Outstanding progress continues to be made and the optimism of a year ago has been reinforced by this year’s reports.

As noted above, several of the groups are now clearly capable of determining in the neighborhood of 100 new protein structures per year. This validates the overall philosophy of the PSI initiative, namely that Phase I would permit individual groups to develop the necessary technology to permit true high-throughput structure determination. A number of the groups have developed highly efficient methods to screen for suitable targets, clone and express new proteins, and to rapidly proceed to structure determination. Methods to systematically improve the solubility and/or folding of proteins have been developed which will be of benefit to molecular and structural biologists in general (not just the PSI groups). Likewise, much improved ways to screen crystals prior to data collection will benefit all macromolecular crystallographers. Continued development of cell-free expression systems will provide an alternative route to deal with intractable proteins and, perhaps more important, make it possible for the first time to use residueand atom-specific isotopic labeling to greatly strengthen NMR structure determination. In parallel with the increasing number of X-ray- and NMR-derived structures, the Protein Data Bank is evolving from an archive for crystallographers into a tool that will make structural information much more readily accessible to the biological community at large.

At the same time, the PSIAC is aware of a number of problem areas that remain. For example, much of the progress that has been made by the PSI is poorly appreciated by the outside community. There is an ongoing need to educate the scientific community on the benefits of the PSI. It was proposed that an article describing PSI progress might be published in a major journal. This could be prepared by NIGMS staff together with the Chair and a subset of the PSIAC. It is also clear that there needs to be a readilyaccessible, widely-known PSI knowledge base where biologists can readily find structural information about any particular protein in which they happen to be interested.

In summary, the PSI Advisory Council remains highly impressed with the progress that has been made. The part of the initiative that was perhaps expected to be the hardest (pipeline and technology development) has gone extremely well. The emphasis now is to communicate the benefits of the PSI to the scientific community at large.