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.
