f this page or responsible for its content.
Roeder awarded Horwitz Prize for untangling transcription A
n d rej Sali, assistant pro f e s s o r,
A l f red P. Sloan re s e a rch fellow
and Sinsheimer scholar, will
p resent todays Friday lecture (Feb. 11).
The topic of his talk will be
Comparative Protein Stru c t u re
Modeling of Genes and Genomes.
S a l i s lab designs methods to theore t-
ically predict three-dimensional stru c-
t u res of proteins. At the core of all the
re s e a rch done in S a l i s lab is compara-
tive modeling. Comparative modeling
uses known protein stru c t u res deter-
mined by experimental methods, such
as X-ray crystallography and nuclear
magnetic resonance (NMR) spec-
t ro s c o p y, to extrapolate the stru c t u re of
other proteins. Sali designed the soft-
w a re program MODELLER to aid in this
p rocess.
Building on the theory that pro t e i n s
with similar sequences have similar
s t ru c t u res, MODELLER allows scientists
to take advantage of current knowledge
and obtain new protein stru c t u res. The
p rogram compares the amino acid
sequence of a protein with an unknown
s t ru c t u re (re f e rred to as the target) to a
p rotein with a known stru c t u re that has
a similar amino acid sequence (the tem-
plate). The pro c e d u re consists of four
steps. The first step is to identify the
template. Next, the sequences of the
template and the target are aligned.
F rom this alignment a thre e - d i m e n s i o n-
al model is built. Finally, the model is
assessed using computational and
experimental methods. MODELLER is
c u rrently used in over 1,000 academic
labs as well as by many pharm a c e u t i c a l
companies.
T h e re are a multitude of puzzles and
challenges that comparative modeling
can help master. Sali, who heads the
L a b o r a t o ry of Molecular Biophysics,
collaborates with other labs at RU a n d
e l s e w h e re that are seeking to learn more
about a particular protein. He also
works on modeling proteins on a larg e
scale and is helping to build the infra-
s t ru c t u re for the fields of structural and
functional genomics.
In todays lecture, Sali will focus on
how comparative modeling can help
model proteins from the massive
amounts of data generated by genome
sequencing projects. Thanks to initiatives
such as the Human Genome Project, sci-
entists now have data for thousands of
gene sequences, as well as whole
genomes of various organisms. However,
in order for this data to have biological
as well as clinical relevance, the func-
tions of the proteins produced by the
gene sequences must be understood.
Since the way a molecule behaves is
l a rgely determined by the intricacies of
its three-dimensional shape, determ i n-
ing the stru c t u res of the proteins identi-
fied in genomics will help elucidate
what the functions of the proteins are
and how abnormalities in proteins can
cause disease. This emerging field is
commonly re f e rred to as stru c t u r a l
genomics.
The future impact that stru c t u r a l
genomics will have on biology and
medical practice promises to be stagger-
ing. With a deeper understanding of
p rotein stru c t u res and their functions,
F E B U A RY 11, 2000 VOLUME 21, NUMBER 16
THE ROCKEFELLER UNIVERSITY
news
&
notes
2
Let your mouse do
the walking
3
Genetic switches
4
Calendar
Friday lectur e : Comparative protein stru c t u re modeling
O
ne of the most fundamental
p rocesses in biology is the way in
which genetic information encod-
ed in DNA is converted into proteins, a
p rocess called gene expression. At diff e r-
ent times in the life of a cell, diff e re n t
genes are expressed, directing the synthe-
sis of proteins in particular sequences and
g roupings. Just as musical instru m e n t s
playing in programmed combinations can
p roduce a symphony, gene expression is
o rchestrated.
The result for the cell can be its orc h e s-
trated development into a liver, heart, or
skin cell, for example, or the decision to
g row or to divide, or to interact with other
cells to form tissues in the body. And
when gene expression goes awry, a cell
may turn cancero u s .
The first step in gene expression is
transcriptionthe switching on of a gene.
DNA provides a sort of musical score, but
what functions as the maestro, telling a
gene to begin perf o rming?
During the last 30 years, RU Professor
Robert Roeder has answered this ques-
tion with seminal contributions, and he
provided much of the information that
scientists know about the transcription
process in animal cells. Last Thursday
(Feb. 3), Roeder was recognized for his
profound impact on science with the
Louisa Gross Horwitz Prize from
Columbia University. The prize, which
Roeder shares with Robert Tjian of the
Howard Hughes Medical Institute at the
University of California at Berkeley and
Pierre Chambon of the Université Louis
Pasteur and the College de France, hon-
ors scientists for outstanding basic
research in biology or biochemistry.
While he has shared many prizes with
Tjian in recent yearsmost notably last
y e a r s Sloan Prize from the General Motors
Cancer Research FoundationRoeders
work laid the foundation upon which dis-
coveries by Tjian, Chambon and others
w e re made.
C u rrent re s e a rch in the Roeder lab
includes elucidating how transcription fac-
tors are activated. Some of these pro t e i n s
o rchestrate cells that mount the bodys
defense against foreign invaders. Other
factors flip the switch that keeps cell divi-
sion in checkor causes tumors when it
malfunctions. By demonstrating how the
function of key factors is altered, Roeders
lab may help clarify the reasons for vari-
ous growth and developmental abnorm a l i-
ties. Ultimately, it may lead re s e a rchers to
c o n t rol these processesand repair their
pathological consequences.
As we become familiar with the fun-
damentals of how genes work, we get
closer to understanding diseases like
cancer, or viral infections like HIV, says
Roeder, the universitys Arnold and
Mabel Beckman Professor and head of
the Laboratory of Biochemistry and
Molecular Biology.
Roeders pioneering studies began
when he was a graduate student at
the University of Washington in the
late 1960s.
My career started in the early days of
understanding what vertebrate genes were
and how they function, Roeder says. I
first became interested in gene activation
because this process is at the center of cell
g rowth and diff e re n t i a t i o n .
Gene activation, the process of tran-
scription, involves making an RNA copy
of the gene from the DNA template.
C o n s t ructing this copy re q u i res enzymes
known as nuclear RNA polymerases,
which Roeder discovered while working
in the laboratory of William J. Rutter. In a
landmark paper published in 1969, he
identified three polymerases, which he
designated I, II and III, responsible for
reading out DNA and synthesizing the
t h ree diff e rent types of RNA. Roeder also
found three distinct groups of pro t e i n
complexes, called accessory factors, that
a re essential for the individual RNA poly-
merases to recognize and copy part i c u l a r
classes of genes.
Roeder was also the first to identify the
general factorsproteins common to the
transcription process for any genefor a
number of diff e rent classes of genes,
including class II genes, the ones that
code for proteins in animal cells. The gen-
eral factor called TFIID is a key member
of this group, because it is the first to bind
to the DNA control element called the
TATA box, a short section of DNA that
Roeder awarded Horwitz Prize for untangling transcription
Professor Robert Roeder receives the Louisa Gross Horwitz Prize from Columbia University President
George Rupp last Thursday (Feb. 3). The Horwitz Prize has become informally known as a Nobel Prize "pre-
dictor," with nearly half of its recipients going on to win the Swedish prize since 1967. President Arnold
Levine received last year s Horwitz Prize. Photo courtesy of Columbia University.
President Emeritus Joshua Lederberg was at the Elysée
Palace in Paris last week to sign the Charter of Paris
written by the World Summit Against Cancer. The char -
ter underscores the commitment of its signers to
ensure the humanitarian treatment and equal partner-
ship of people with cancer, create optimal research
environments, accelerate the development and applica-
tion of proven and emerging technologies, address the
global burden of cancer, and design anti-cancer strate -
gies to meet local needs.
Photo courtesy of Joshua Lederburg.
Andrej Sali, RU assistant professor and Alfred P.
Sloan research fellow, will present todays Friday
lecture.
Photo by Robert Reichert.
see Friday lecture
,
page 2
see Untangling transcription
,
page 3 2
news
&
notes
F E B U A RY 11, 2000
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