David N. Garboczi, Ph.D.

Investigator

Dr. Garboczi obtained his Ph.D. from the University of Oregon after performing his predoctoral research at the Johns Hopkins School of Medicine in the biochemistry of the ATP synthase of mammalian mitochondria. Following postdoctoral research in molecular immunology at Harvard University, he joined the Structural Biology Section in 1997 as a tenure-track investigator.

Description of Research Program

• T-cell receptors. We are studying alpha/beta and gamma/delta T-cell receptors (TCR) to more fully understand their recognition of antigens and their activation in an immune response. In contrast to alpha/beta T-cell receptors, which recognize peptide antigens bound to major histocompatibility complex molecules (MHC), gamma/delta TCRs can directly recognize antigens in the form of intact proteins or non-peptidic compounds. About 5% of all human peripheral blood T cells bear gamma/delta TCRs, most of which recognize a number of non-peptidic phosphorylated antigens. We have determined the structure of a human gamma/delta TCR isolated from a T-cell clone that is activated by these phosphoantigens. The orientation of the variable and constant domains of the gamma/delta TCR is unique when compared to alpha/beta TCRs or to antibodies. The complementarity-determining regions of the V domains exhibit a chemically reasonable binding site for a phosphorylated antigen.
• Malaria. The malaria parasite invades and prospers in a variety of tissues such as the skin, blood, liver, gut, and salivary glands of its human and mosquito hosts. This invasion of many kinds of cells implies that the parasite must make use of a diverse cell biology of receptor-ligand interactions. By determining the three-dimensional structures of receptors, ligands, and receptor-ligand complexes and by studying their associations in solution, we are examining the macromolecular interactions that allow the parasite to specifically invade a particular cell type.
  
  The surface proteins of the malaria parasite are truly frontier projects for structural biologists. Most of the protein sequences have no similar sequences known, and therefore, there is not a predicted shape or fold for many surface proteins. Some proteins are known to be essential for cell invasion; others are essential for the parasite life cycle, but their function is not known. The parasite receptors, being on the cell surface, are also prime candidates for the development of anti-malarial vaccines as natural immunity to malaria appears to correlate with immune responses to cell surface receptors. Through these studies, we will reveal the overall shapes and the specific interactions of important receptors on the parasite and gain a greater understanding of the fundamental biology of the malarial parasite.

Research Group Members

Timothy J. Allison, Brandt R. Burgess, Scott C. Garman, Michael M. Klein, Ajay Saxena, Kavita Singh, Hua-Poo Su.

Selected Publications

(Search PubMed.)

Garman SC, Simcoke WN, Stowers AW, Garboczi DN. Structure of the C-terminal domains of merozoite surface protein-1 from Plasmodium knowlesi reveals a novel histidine binding site. J Biol Chem. 2003. 278: 7264-7269.

Garman SC, Hannick L, Zhu A, Garboczi DN. The 1.9 Å structure of a N acetylgalactosaminidase: molecular basis of glycosidase deficiency diseases. Structure. 2002. 10: 425-434.

Allison TA, Winter CC, Fournie JJ, Bonneville M, Garboczi DN. Structure of a human gamma delta T-cell antigen receptor. Nature. 2001. 411: 820-824.

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