Glen Spraggon, D.Phil.
Associate Director of Structural Biology

With the explosion of genomic information over the last few years, structural biology has become more important than ever. The Structural Biology Program at GNF is dedicated both to obtaining atomic resolution information on target molecules using x-ray crystallography and to developing and employing new technologies in x-ray crystallography.  Projects, which generally involve collaborations between many groups at GNF, range from the determination of protein function from structure to the development of novel inhibitors by structure-aided drug design techniques. These are coupled with the development of new technologies for various structural genomics projects, taking advantage of GNF’s automated protein expression, purification, and crystallization facilities. Regular access to a synchrotron beamline equipped with automounter at the Advanced Light Source at the University of California, Berkeley, ensures data collection to be efficient and of the highest quality.

Structure Aided Drug Design
An important early step in drug discovery is the determination of the exact binding modes of ligands to their target proteins. Collaborations between medicinal chemists, computational chemists, and our NMR experts have provided an effective pipeline for the optimization of potential compounds via Structure-Activity Relationships (SAR) combined with Structure Aided Design. The structural biology group has been involved in a number of therapeutic areas such as infectious diseases, autoimmune disease, and oncology and is also involved in developing screening techniques by x-ray crystallography and NMR such as Fragment Based Screening of macromolecular crystals for inhibitor optimization.

Figure 1
a) Crystal structure of inositol 1,4,5 triphosphate-3 kinase isoform B showing novel beta strand bridge between subunits. (Chamberlain, et al; Biochemistry 44: 14486)
b) Crystal structure of Cathepsin S in complex with an arylaminoethyl compound showing co-ordination of zinc ion to no-covalent inhibitor and active site serine. (Tully, et al; Bioorg Med Chem Lett 16; 5112)
c) Ankyrin repeat of ion channel TrpV2 at 1.6 Å. (McCleverty, et al; Prot Sci 15; 2201)

Application of Technologies
GNF’s unique high throughput screening tools have enabled the discovery of several new and interesting proteins involved in a variety of important regulatory processes. To provide atomic-level information for function studies, we solve the structures of these targets.

In addition, we have studied axon guidance proteins, proteins involved in the progression of the apoptotic signal through the intrinsic mitochondrial cell death pathway, and members of the Transient Receptor Potential (TRP) channel family.

Currently, we are applying our efforts to studying the structures of protein families and pathways including kinases, proteases and proteins involved in inositol phosphate metabolism.
 
Structural Genomics
The National Institutes of Health has identified structural genomics—the study of the structure of genes and proteins to illuminate their function—as a key area of need for the scientific community and has established the Protein Structure Initiative as a follow-on to the Human Genome Project. GNF participates in this effort as a member of the Joint Center for Structural Genomics (http://www.jcsg.org).

Our participation in the JCSG allows us to advance technology development useful to GNF and the structural biology scientific community. The structure pipeline that we have developed within the JCSG is currently producing novel protein structures at a rate of over 100 per year including many unique protein folds and structural features.  These structures provide tremendous value to the basic scientific community and have been the source for numerous collaborative studies exploring these structures’ biological significance.

A selection of structures solved by the JCSG as part of the NIH Protein Structure Initiative

Selected Publications

• Hampton EN, Knuth MW, Li J, Harris JL, Lesley SA, Spraggon G. The self-inhibited structure of full-length PCSK9 at 1.9 A reveals structural homology with resistin within the C-terminal domain. Proc Natl Acad Sci U S A 2007;104(37):14604-9.
• McCleverty CJ, Hornsby M, Spraggon G, Kreusch A. Crystal structure of human Pus10, a novel pseudouridine synthase. J Mol Biol 2007;373(5):1243-54.
• Okram B, Nagle A, Adrian FJ, Lee C, Ren P, Wang X, Sim T, Xie Y, Wang X, Xia G, et al. A general strategy for creating "inactive-conformation" abl inhibitors. Chem Biol 2006;13(7):779-86.
• Chamberlain PP, Sandberg ML, Sauer K, Cooke MP, Lesley SA, Spraggon G. Structural insights into enzyme regulation for inositol 1,4,5-trisphosphate 3-kinase B. Biochemistry (Mosc) 2005;44(44):14486-93. 
• Kreusch A, Han S, Brinker A, Zhou V, Choi HS, He Y, Lesley SA, Caldwell J, Gu XJ. Crystal structures of human HSP90alpha-complexed with dihydroxyphenylpyrazoles. Bioorg Med Chem Lett 2005;15(5):1475-8.

Please click here for a full list of group publications