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Department of Molecular
Biology
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One of the major strengths of the Department of Molecular Biology is analysis of the three-dimensional structures
of proteins and nucleic acids, which has led to a more detailed understanding of the mechanisms by which these biological molecules function. This, in turn,
provides important insights into whole organisms, disease states, and potential therapies to improve human health.
One of the major strengths of the department is analysis of
the three-dimensional structures of proteins and nucleic acids,
which has led to a more detailed understanding of the mechanisms
by which these biological molecules function. This, in turn,
provides important insights into whole organisms, disease states,
and potential therapies to improve human health.
The department has several groups using x-ray crystallography to determine the three-dimensional structure of
proteins. One lab solved an x-ray crystal structure that provides the first detailed glimpse of a membrane transporter protein, which is expressed in
almost all organisms and sits in the cell membrane, moving other molecules in and out. Harmful bacteria and certain cancer cells use these transporters to
undermine the potency of antibiotics and chemotherapy drugs by pumping the drugs out before they have a chance to work. The structure is a breakthrough
and may ultimately have a profound impact on the development of novel therapeutics, opening the door for scientists to design a new class of drugs
that patients would take in conjunction with antibiotic or chemotherapeutic agents to increase their efficacy.
In the area of virus structure, the first detailed insights into the conformational changes that accompany
virus maturation were obtained by a research group in the department. A molecular-level description of these conformational changes is of great
biomedical significance because of the essential role the changes play in transformation of viral precursors into infectious virions.
In another exciting finding on the viral front, a group in the department elucidated the structure of an antibody
that effectively neutralizes human immunodeficiency virus (HIV), making it unable to invade cells. One of the most compelling medical challenges today is
to develop a vaccine that will provide complete prophylactic protection to someone who is exposed to the virus. An important part of such a vaccine will
be an effective neutralizing antibody against HIV, which would circulate through the blood, and track down and kill the virus. Normally, the antibodies
that the body produces to fight HIV are ineffective, so this work is a large step forward in the effort to design a vaccine against the HIV virus.
Investigators in two groups in the department were awarded a structural genomics pilot grant from the National
Institutes of Health to establish a large-scale, multi-institutional consortium for research in this new discipline. The grant will enable the researchers to
develop new technologies for high-throughput structure determination and should accelerate therapeutic drug design based on the knowledge reaped from the human
genome.
Another major new initiative, funded by the NIH, will establish a large-scale, multi-institutional consortia
for research in the field of functional glycomics, the scientific pursuit of identifying and studying all of the carbohydrate molecules produced by an
organism.
The department also is a leader in nuclear magnetic resonance spectroscopy, a technique that enables scientists to
determine the structure-function relationships of molecules. The most powerful, high-resolution nuclear magnetic resonance (NMR) spectrometer built to date
resides at TSRI. Referred to by the frequency at which it operates, 900 MHz, this instrument is the centerpiece of the institute's NMR structural studies.
With 10 instruments at or above 500 MHz, TSRI now has one of the largest NMR facilities in the world.
The department has several groups with strong programs in NMR structure determination, studying protein¬protein interactions, solution structures of proteins and nucleic
acids, and the partially folded states of proteins.
One team solved the structure of a protein, called hypoxia inducing factor (HIF-1a),
that is crucial for cancer tumor growth. Blocking HIF-1 has already proven to
be an effective way of stopping tumor growth in animal models, and the unforeseen
molecular details revealed by the structure are like a roadmap for the development
of future anti-cancer therapeutics.
Another team has determined the structure of a large ribonucleoprotein complex from the 30S subunit of the
ribosome--the large molecular machine that synthesizes proteins in cells. The
structure provides important insights into ribosomal structure and the role of
protein conformational change in ribosome assembly.
Moreover, the physiological role of the molecules of interest to department investigators provides important
insights into disease states and how these states can be blocked or modified to
improve health. Not surprisingly, many of the researchers in the department are
interested in the entire range of biology at the molecular level--from the most
detailed structures to the broadest questions of how they function.
In the field of RNA catalysis, which focuses on the biochemical reactions that are catalyzed by RNA rather
than by proteins, it was thought that all catalytic RNA molecules, or
"ribozymes," used metal ions to carry out the catalysis. But one research group
established that a "hairpin" shaped ribozyme requires no metal ions for its
catalytic activity. This finding raises the exciting possibility that
functional groups on the RNA itself participate directly in the chemistry of
catalysis.
Another group has developed a novel approach to incorporating unnatural amino acids into proteins. The method
provides a powerful new tool for studying protein function and creates new
opportunities for protein engineering. By using this approach, novel proteins
with unusual chemical composition and perhaps enhanced or emergent properties
could be evolved and expressed in abundance.
Important advances have also been made in the elucidation of the fundamental molecular processes involved in
control of eukaryotic cell division. A group in the department has identified a
critical protein that regulates cyclin E, a protein that controls DNA
replication. Mutant forms of this protein occur in several tumor cell lines,
suggesting that it may function as a tumor suppressor.
Another advance in molecular genetics came from a team of investigators who
identified the "resolvase" enzyme Mus81 from the fission yeast Schizosaccharomyces
pombe, and its human analog. This is one of the most important enzymes involved
in genetic recombination, the process that occurs when chromosomes from the
mother and father become paired, and it may be responsible for generating genetic
diversity during sexual reproduction. The identification of a human resolvase
may also have a profound effect on cancer therapy because the enzyme also has
an important role in aiding in the repair of damaged DNA. Members of the same
team have also characterized an enzyme, Cid13, that regulates the expression
of a gene in S. pombe, determining that the enzyme was involved
in RNA metabolism. This finding may have implications for the treatment of cancer.
In addition, several members of the department have been working with catalytic antibodies and have made major
advances in their design and evolution. Antibodies are specific proteins
secreted by immune cells that recognize specific markers (antigens) derived
from, for instance, components of bacteria. Catalytic antibodies have enzymatic
activity in addition to their recognition function and can be used for basic
science, for instance speeding up chemical syntheses, or as the basis for novel
therapies. Members of the faculty have used catalytic antibodies to activate
masked anticancer "prodrugs" within human colon and prostate cancer cell lines
as potential agents for the treatment of these cancers.
Finally, two investigators in the department study the hypocretins--two excitatory neuropeptides expressed by a
few thousand neurons in the brain that are part of a complex circuit that
integrates aspects of energy metabolism, cardiovascular function, hormone
homeostasis, and sleep-wake behaviors. The TSRI investigators' work may lead to
a better understanding of the basis of sleep regulation and more effective
treatments for narcolepsy.
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