Jon Clardy, Chemistry and Chemical Biology

The Clardy laboratory works in what is now called chemical biology. Starting from an interest in natural products, they are trying to answer questions involving

chemical ecology (what organisms make unusual natural products and why),

biosynthesis (how is a natural product made),

mechanism of action (what is the macromolecular target of a biologically active natural product),

structural biology (what is the three-dimensional structure of a natural product bound to its macromolecular target), and

structure-based drug design (how could an even better ligand for a macromolecular target be made).

One example of this work centers on the natural product rapamycin, originally isolated because of its antifungal activity from a soil microorganism found on Easter Island. When a related compound, FK506, was shown to be a potent immunosuppressive agent, rapamycin was reinvestigated and found to be an equally powerful cell cycle arrest agent. Currently, rapamycin is being investigated for possible use to treat cancer and to prevent the rejection of transplanted organs. Rapamycin works by binding tightly to (FKBP) FK506 binding protein.

The structure of the FKBP-rapamycin complex was solved using X-ray crystallography by the Clardy laboratory in 1991. Rapamycin does not simply inhibit FKBP; the FKBP-rapamycin complex binds to and inhibits another protein called (FRAP) FKBP-rapamycin associated protein. In 1996, the Clardy group used X-ray crystallography to show how rapamycin simultaneously binds two different proteins, FKBP and FRAP, by occupying two very different binding pockets.

Close relatives of the FRAP protein are involved in cell cycle progression and repair, and defects in these proteins can lead to diseases such as cancer. Rapamycin's unusual mechanism of action, its ability to dimerize two different proteins, has inspired the design of partially synthetic analogs that can be used to control cellular processes. Part of the ongoing research of the Clardy group involves improving the design of such cellular control agents.

Recently, the laboratory has also focused on structure-function characterizations of a class of enzymes that may be highly relevant to cell growth regulation and cancer, namely the methionine aminopeptidases, which have been implicated in angiogenesis. The Clardy group is also engaged in various collaborative studies with other participating faculty on this proposal to obtain X-ray crystallographic structures of important cellular signaling molecules (see Section B3b, below).