The research within the Koh group focuses on the rational
molecular design and synthesis of molecules which can serve to address
important biological problems.
Chemistry may provide new keys to
control gene expression.
The sequencing of the human genome
represents one of mankind's greatest achievements. However, the genome
also holds many promises and secrets yet to be realized. Remarkably,
the genome contains fewer genes than many expected and indeed most of the
genome (greater than 90%) does not encode genes but may be involved in
controlling the expression and replication of the genes. Effectively,
we now know the component parts but not what the parts do or how the parts
are wired together.
We are working on several projects
to develop new methods selectively and remotely control gene expression
that will ultimately allow us to understand how our genes are expressed
in a controlled dynamic system.
The nuclear hormone receptors are Nature's tool for remotely regulating gene transcription using the small organic molecules we know as hormones. By altering the structure of these proteins by site-directed mutagenesis, we are generating new transcription control systems that respond to custom designed hormones that can be used for controlling gene therapies in medicine and for studies in biology.
We are also using our knowledge of crystal structures
of hormone receptor members to design hormone analogs whose agonist (transcripton
activating) properties are masked by photo-labile protecting groups.
This enables us to release active agonists and activate genes using light.
This new technique may enable to use focused light sources to activate
gene expression at unprecedented levels of spatial and temporal resolution
allowing us to address important question about the role of patterned gene
expression in development, cell migration and metastasis and intercellular
communication.
Can Molecular Design Compensate for Human Disease?
Naturally occurring mutations to hormone receptors are
known to be associated with human genetic diseases such as rickets, RTH
and certain forms of prostate cancer, diabetes, and leukemia. Most
often these mutations prevent the natural ligand from fitting into the
binding site of the receptor. Recently we have demonstrated that
we can use structural information about these mutant receptors to design
custom made hormones that selectively recover activity to mutant thyroid
hormone receptors associated with the disease RTH in vitro. We believe
this to be the first example of a molecule being designed to complement
a mutation associated with human genetic disease.
The interface of chemistry and biology offers a vast array of opportunities for a new generation of chemists. Organic chemists can no longer simply copy nature's molecules in hopes to find solutions to today's current health problems. Armed with the traditional chemical skills of synthesis and design, chemists can uniquely understand the molecular basis for many biological problems and create unique molecular solutions.
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Last updated 06/25/02
