Molecular Biology - The Scripps Research Institute

160 MOLECULAR BIOLOGY 2005
Chairman’s Overview
Research in the Department of Molecular Biology
encompasses a broad range of disciplines, extending
from structural and computational biology at
one extreme to molecular genetics at the other. During
the past year, our scientists continued to make rapid
progress toward understanding the fundamental molecular
events that underlie the processes of life. Major
advances have been made in elucidating the structural
biology of signal transduction and viral assembly, in
understanding mechanisms of viral infectivity, in determining
the structure of membrane proteins, in understanding
the molecular basis of nucleic acid recognition
and DNA repair, and in determining the mechanism of
ribosome assembly. Progress was made in elucidating
the molecular events involved in regulation of the cell
cycle, in tumor development, in induction of sleep, in
the molecular origins of neuronal development and of
CNS disorders, in the regulation of transcription, and in
the decoding of genetic information in translation. Finally,
new advances were made in the design of novel low
molecular weight compounds that can specifically regulate
genes and in the area of biomolecular engineering,
building novel functions into viruses, antibodies, zinc
finger proteins, RNA, and DNA. Progress in these and
other areas is described in detail on the following pages,
and only a few highlights are mentioned here.
Published by TSRI Press ®. ©Copyright 2005,
The Scripps Research Institute. All rights reserved.
Peter E. Wright, Ph.D.
Structural biology continues to be a major activity
in the department, and many new x-ray and nuclear
magnetic resonance structures of major biomedical
importance were completed during the past year. Among
the highlights was the determination, in Ian Wilson’s laboratory,
of the first structure of a human Toll-like receptor,
a protein that plays a key role in the innate immune
system as a sensor of molecules associated with the cell
wall and genetic material of pathogenic bacteria. Dr. Wilson
and his coworkers also reported structures of the
protein CD1a, another key receptor in the innate immune
response, and of an antibody that neutralizes most strains
of HIV. Other advances came in the area of membrane
protein crystallography: Geoffrey Chang and colleagues
determined the structures of 2 proteins (MsbA and EmrE)
involved in drug transport and the development of drug
resistance in bacteria and cancer cells, and David Stout
and James Fee determined the structure of a cytochrome
ba 3 oxidase. Finally, the Joint Center for Structural
Genomics, directed by Ian Wilson, was selected by the
National Institutes of Health as 1 of 4 large-scale centers
for high-throughput determination of protein structures.
Several research groups are working in areas directly
related to drug discovery and protein therapeutics. Joel
Gottesfeld and colleagues have developed a small DNAbinding
molecule that turns off the gene for histone H4
and blocks replication in a wide variety of cancer cells.
The compound is active in vivo and blocks the growth
of tumors in mice. Research in the laboratory of Carlos
Barbas is directed toward genetic reprogramming of
tumor cells via engineered zinc finger transcription factors.
These artificial transcription factors are powerful
tools for determining the function of genes in tumor
growth and progression and have potential applications
in cancer therapy. John Elder and colleagues are studying
development of resistance to drugs that target the
HIV protease. A complementary approach to the same
problem is being taken by Arthur Olson and researchers
in his laboratory in their FightAIDS@Home program.
This program is a large-scale computational effort in
which a grid of personal computers distributed around
the world is used to design effective therapeutic agents
that target the HIV protease. Raymond Stevens and
coworkers have engineered a phenylalanine ammonia
lyase enzyme as a potential injectable therapeutic agent
for treating phenylketonuria. Finally, Paul Schimmel and
colleagues have identified a naturally occurring fragment
of tryptophanyl-tRNA synthetase that is highly potent in
arresting angiogenesis and is being introduced in a clinical
setting for treatment of macular degeneration.