My Research
The interactions of proteins with other biological molecules are central features of all biological processes. A molecular understanding of these interactions requires a knowledge of both the three dimensional structures and the biological functions of the molecules involved. Because the most generally applicable method of determining three dimensional structures of biological macromolecules is X-ray crystallography, this technique is central to how we approach biological questions.

Primary Focus
A major focus of the lab is in structural genomics. The genome sequencing projects are producing a vast database of sequence information and provide a list of the proteins and their sequences that are used by that organism. The next logical step is to ask what these proteins look like. Fortunately, in any particular organism most of the proteins are similar in sequence and structure to proteins from many other organisms. Consequently a representative structure from a protein sequence family provides a model for all of the proteins in that family. The Midwest Center for Structural Genomics, funded by the NIH Protein Structure Initiative, has as its goal the determination of representative structures for each of the major sequence families. This multi-institutional center is developing methods for high throughput structure determination and applying those methods to determine the structures of a large number of target proteins.

Secondary Focus
A second focus is utilization of the results of the structural genomics effort to expand our understanding of biology. The existence of large databases of protein sequences and structures, combined with the fact that many of those proteins have not been functionally characterized, has reversed the historic pathway leading from function to structure and sequence. Now we need to utilize the sequence and structure information available for proteins to suggest possible functions. The existence of large families of proteins with conserved sequences and structures that are represented in a wide range of organisms but are functionally uncharacterized highlights fundamental areas of biology that are unexplored. Therefore, we are selecting particularly interesting proteins from our structural genomics efforts for further studies of their biological functions.

In addition to providing a library of the most biologically important protein structures, the international structural genomics initiatives provide important information for studies of enzyme mechanisms and the structural basis for catalysis, nucleic acid-protein interactions, protein-protein interactions, and allosteric regulation of protein function. Because the majority of the proteins that have been targeted for structure determination by the Midwest Center for Structural Genomics are from bacterial pathogens, the resulting library of structures may additionally provide useful starting points for structure aided drug discovery of novel antimicrobials.

For more information, see
http://www.mcsg.anl.gov
http://www.nigms.nih.gov/Initiatives/PSI/
http://www.ls-cat.org