The 2008 Schering-Plough Research
Institute Award: Scott A. Strobel
The Schering-Plough Research Institute Award will
be presented to Scott A. Strobel, a Howard Hughes
Medical Institute professor at Yale University. The award
was established to recognize young investigators for outstanding research at an early stage of their careers. Strobel
will present his award lecture titled, “Three Views of RNA
Catalysis: Ribozymes, Ribosomes, and Riboswitches” on
Sunday, April 6, at 2: 15 p.m.
“I first met Scott when he was a postdoc in Tom Cech’s
lab and I was on sabbatical there,” recalls Thomas A. Steitz,
Sterling Professor of Molecular Biophysics and Biochemistry at Yale University and Howard Hughes Medical Institute
Investigator. “I was so impressed with him that I worked
hard to encourage his joining the faculty at Yale, which wonderfully he did. I have watched and marveled at his scientific
development over the past 11 years at Yale. In my view,
Scott has now developed into a major leader at the interface between chemical biology and structural biology.”
Strobel attended Brigham Young University where he
earned his B.A. in 1987. He then went on to the California
Institute of Technology where he worked with Peter B.
Dervan and earned his Ph.D. in 1992, studying the site-specific cleavage of genomic DNA by triple helix formation.
Next, he did a postdoctoral fellowship at the University
of Colorado, studying molecular recognition of an RNA
duplex by a ribosome with Thomas R. Cech. In 1995,
Strobel joined the faculty of the Department of Molecular
Biophysics and Biochemistry at Yale University, where he
currently remains today as chair of the department and is
also an HHMI professor.
“Scott is a chemical biologist in the best sense of the
term,” says Peter B. Moore, Sterling Professor of Chemistry
at Yale University. “Much of the work his group has done
derives from his ability to synthesize organic molecules that
he can use as tools to solve important biological problems.
For example, shortly after coming to Yale he made important contributions to the development of an elegant technique for determining the role of specific atoms in maintaining the structure and activities of RNA molecules.”
The technique, called NAIM (nucleotide analog interference method), involved the tagging of nucleotide analogs
(such as inosine substituted for guanosine to test the
importance of the amino group on
the base) with a phosphorothioate,
allowing positions of incorporation to
be revealed by iodine cleavage. Using
this technique, Strobel and his colleagues were able to look at multiple Strobel
functional groups on bases and on
ribose sugars, and to build credible and testable models of
RNA active sites such as those in the catalytic site of the
group I RNA intron ( 1). NAIM has also been used by several
other labs to identify functional groups essential for the
activities of RNA, including protein binding.
Next, Strobel solved the crystal structure of the ribosome group I intron in two of its catalytically relevant states
( 2, 3). These structures revealed how the intron uses
novel RNA motifs to select the 5’- and 3’-splice sites and
the manner in which it is able to coordinate metal ions to
promote the chemical reaction. The two structures were
the first of the complete group I intron and were the first
to establish conclusively how metal ions were utilized in
catalyzing the reaction.
Strobel’s research has also focused on the mechanism
of the peptidyltransferase reaction catalyzed by the large
ribosomal subunit. He and his colleagues synthesized a
series of substrate and transition state analogues for use in
biochemical and crystallographic studies to elucidate the
mechanism of the reaction. Recently, he performed a set
of kinetic isotope effect experiments that have characterized the transition state of the peptidyltransferase reaction.
“Scott is an outstanding synthetic organic chemist,
biochemist, and molecular biologist who sees no boundaries between those fields and therefore transverses them
effortlessly. In addition, he is an extraordinarily innovative
teacher and mentor,” says Thomas R. Cech, President of
Howard Hughes Medical Institute and Distinguished Professor at the University of Colorado, Boulder.
REFERENCES
Strobel, S. A., and Shetty, K. (1997) Defining the chemical groups essential for
Tetrahymena group I intron function by nucleotide analog interference mapping.
Proc. Natl. Acad. Sci. U.S.A. 94, 2903-2908.
Adams, P. L., Stahley, M. R., Kosek, A. B., Wang, J. and Strobel, S. A. (2004) Crystal
structure of a self-splicing group I intron with both exons. Nature 430, 45-50.
Stahley, M. R., and Strobel, S. A. (2005) Structural evidence for a two-metal-ion
mechanism of group I intron splicing. Science 309, 1587-1590.
