Research interests of James C. Sacchettini, Ph.D.

My laboratory studies the interactions between proteins and their ligands or substrates. We use several techniques in the examination of the molecular details of these types of interactions including X-ray crystallography, microcalorimetry and molecular biology. An area of interest for several years has been proteins and enzymes involved in lipid biosynthesis. We are also applying these techniques to the understanding of the structural basis of the cellular immune response. This is being done through a concerted effort to determine the 3-D structures of several major histocompatability complexes (MHCs) with specific antigenic peptides bound, as well as the T-cell receptor. These studies have permitted many insights into how cells notify the immune system of their infection. A third major focus in the laboratory is in the field of rational drug design. Our approach is to first determine the 3-D structure of a target enzyme and then use this information to design inhibitors that will bind to the enzymes active site. We have now designed and synthesized several compounds which are drug candidates against tuberculosis.

Representative Publications

Adamski-Werner SL, Palaninathan SK, Sacchettini JC, Kelly JW. (2004) Diflunisal Analogues Stabilize the Native State of Transthyretin. Potent Inhibition of Amyloidogenesis. J Med Chem. 47(2): 355-374.

Smith CV, Sharma V, Sacchettini JC. (2004) TB drug discovery: addressing issues of persistence and resistance. Tuberculosis (Edinb). 84(1-2): 45-55.

Zhang F, Lucke C, Baier LJ, Sacchettini JC, Hamilton JA. (2003) Solution structure of human intestinal fatty acid binding protein with a naturally-occurring single amino acid substitution (A54T) that is associated with altered lipid metabolism. Biochemistry. 42(24): 7339-47.

Sharma V, Arockiasamy A, Ronning DR, Savva CG, Holzenburg A, Braunstein M, Jacobs WR Jr, Sacchettini JC. (2003) Crystal structure of Mycobacterium tuberculosis SecA, a preprotein translocating ATPase. Proc Natl Acad Sci U S A. 100(5): 2243-8. Epub 2003 Feb 26.

Smith CV, Huang CC, Miczak A, Russell DG, Sacchettini JC, Honer zu Bentrup K. (2003) Biochemical and structural studies of malate synthase from Mycobacterium tuberculosis. J Biol Chem. 278(3): 1735-43. Epub 2002 Oct 21.