Joseph P. Noel
e-mail: noel@salk.edu |
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Our laboratory is interested in unraveling the chemistry of a number of biological processes. In particular, our work is based on a structural framework that serves as a useful starting point for more functional analyses. To accomplish our research goals, we use macromolecular x-ray crystallography to decipher the structure of proteins and molecular biology, spectroscopy, and chemical synthesis to probe structurally derived hypothesis about the function of the systems under study. Broadly speaking, our research falls into two categories, mechanisms governing signal transduction pathways and the mechanisms underlying the biosynthesis of plant natural products including terpenoids, flavonoids, and alkaloids.
In the area of signal transduction, the objective is to gain a structural and functional understanding of cellular switches governing membrane associated tyrosine phosphorylation and dephosphorylation and the role of serine/threonine phosphorylation in mitotic progression. A number of group members are focused on understanding how receptor protein-tyrosine phosphatases (RPTPs) are regulated at the plasma membrane. We are examining the structure /function relationships governing signalling through a canonical RPTP, namely RPTPalpha.
Our interest in the cell cycle has grown out of our work on an essential eptidyl-prolyl-cis-trans isomerases (PPIases) known as Pin1 (see figure). Pin1 is unique among a large and structurally diverse family of PPIases in that it displays a unique specificity for the targets of proline-directed kinases such as cyclin-dependent kinases so important in cell cycle regulation. Pin1 specifically recognizes the minimal cdc2 phosphorylation site, -P.Ser (P.Thr)-Pro-. We are continuing to examine Pin1 and have expanded our work to include other proteins that are phosphorylated in a cell cycle dependent fashion. In addition, we have recently begun work on a so-called HECT domain or ubiquitin ligase that is central to the protein degradation pathway in all cells.
In the area of natural product biosynthesis,
the scientific objective is to understand the stereochemical principles
that govern the biosynthesis of pharmaceutically useful natural products
including terpenoids and flavonoids, and alkaloids. Our most recent
work on cyclic terpene production has allowed us to manipulate the target
enzyme 5-epi-aristolochene synthase for the production of novel cyclic
terpenes. Finally, we have recently determined the crystal structure
and stereochemical mechanism of chalcone synthase (CHS). CHS plays a
central role in the defense response of many plants and provides precursors
for pigment production and nodulation inducers. Using the structure,
we have successfully determined the mechanism controlling product specificity
in the related enzymes stilbene synthase (resveratrol) and acridone
synthase (acridine alkaloid).
Majeti, R., Bilwes, A.M., Noel, J.P., Hunter, T. and Weiss, A. (1998). Dimerization-Induced Inhibition of Receptor Protein Tyrosine Phosphatase Function Through an Inhibitory Wedge. Science 279: 88-91.
Ranganathan, R., Lu, K.P., Hunter, T. and Noel, J.P. (1997). Structural and Functional Analysis of the Mitotic Rotamase Pin1 Suggests Substrate Recognition is Phosphorylation Dependent. Cell 89: 875-886.
Mathis, J.R., Back, K., Starks, C., Noel, J., Poulter, C.D. and Chappell, J. (1997). Pre-steady-state study of recombinant sesquiterpene cyclases. Biochemistry 36: 8340-8348.
Noel, J.P. (1997). Turning off the Ras switch with the flick of a finger. Nature Structural Biology 4: 677-680.
Starks, C.M., Back, K., Chappell, J. and Noel, J.P. (1997). Structural Basis for Cyclic Terpene Biosynthesis by Tobacco 5-Epi-Aristolochene Synthase. Science 277: 1815-1820.
Bilwes, A.M., Hertog, J.D., Hunter,
T. and Noel, J.P. (1996). Structural basis for inhibition of receptor
protein-tyrosine phosphatase alpha by dimerization. Nature 382:555-559.
Joseph Noel received his Ph.D. from the Ohio State Univeristy and was a postdoctoral fellow at Yale University.
