Mid-Course Review – Report on the Structural Biology Working Group Membrane Proteins

Executive Summary

The panel members listed above met on January 4, 2008 to conduct a mid-course review of the two Centers for Innovation in Membrane Protein Production that were awarded by the Structural Biology Roadmap Working Group to address bottlenecks in membrane protein structural biology. We heard presentations by NIGMS staff members and by the PIs from the two Centers. We were also given extensive written documentation on the Centers which included the original grant proposals, third year progress reports, and presentations from a joint Center meeting held in November 2007 that also included Roadmap participants holding P01, R01, and R21 awards. We were asked to evaluate the overall success of the initiative and questions specific to the two Centers including scientific progress, center management, program management, and transition planning options for funding. Our findings are summarized below:

1. The SBRWG initiative is successfully promoting research on membrane protein expression, purification, characterization, and structure determination. The two Centers are staffed by extraordinarily talented scientists and they are doing state of the art research on membrane protein structural biology. We were impressed with the breadth of experiments conducted, and also with the diversity of approaches taken by the Centers to improve membrane protein production. Both Centers have developed new research tools, and both have solved high profile structures. One striking example is the β2 adrengeric receptor structure solved recently through a collaboration that included an R21 Roadmap participant (Kobilka) and the JCIMPT Center (Kuhn and Stevens groups). While the Centers were formed just three years ago, they are likely to have a major influence nationally and internationally on membrane protein research.
    
2. The panel was very impressed with the scientific progress both Centers are making. A description of the broad range and number of experiments is given in the body of the report. Clearly the approaches and reagents being developed will be useful to the membrane protein community for characterizing new membrane proteins and solving structures. Both Centers maintain websites, but the panel found that better dissemination of knowledge could be achieved. The community would benefit from learning which approaches work and which do not, and we suggest several solutions: updating/expanding the websites to educate the community, expansion of the very successful Membrane Protein Production and Technologies meeting to include membrane protein structural biologists not funded through the Roadmap program, and establishing training workshops that would teach ‘students’ the various techniques and approaches employed at the Centers.
    
3. The Centers are well managed internally and the program is well managed by NIGMS staff members. In particular, the panel found that the focus of the program, namely to allocate resources to improving membrane protein production, is correctly placed. Producing sufficient quantities of functional and homogeneous membrane proteins was the limiting factor for structural studies when the Centers were established and it remains so today. Even though the Centers are making significant progress, membrane protein production is still very challenging and much more must be learned to significantly advance the field.
    
4. The question of transition planning options for funding once the initial five year awards end is difficult to answer. The Centers are making excellent progress, having an impact on the community, and are poised to make significant contributions to the field. We strongly advise continued support. Although we were specifically charged with reviewing the Centers’ impact on the SBRWG initiative, we were also very impressed with the research being done through the R01 and R21 Roadmap awards and view this as an integral component of the program. We favor that additional R01 and R21 funding should go along with a possible extension of this initiative, whichever way it may be funded.