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FRISC: The Faculty Research Interests Science Comparator |
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Professor of Biochemistry
Biological Chemistry
Molecular Biophysics
Office: (214) 648-5009
FAX: (214) 648-8954
Email: betsy@chop.swmed.edu
Home Page: Goldsmith Lab
My laboratory is studying the structural basis of cell
signaling and enzyme regulation using primarily single crystal diffraction studies of
proteins.
Protein kinase cascades interpret intracellular signals
from hormones and cytokines. We are presently studying the structure of members of the MAP
kinase family, including ERK2, p38, and JNK, and the upstream enzymes MEK1, MKK3, and
MKK6. Of particular interest is how these kinases are regulated by phosphorylation and
changes in states of oligomerization.
We are also addressing the problem of how to make specific
protein kinase inhibitors. Protein kinases are ubiquitous signal transducers in cells, and
thus targets for therapeutic intervention for a variety of diseases. We have determined
the structural basis of specificity for several inhibitors that are selective for
individual MAP kinases. These results are being used to design new inhibitors.
One of the most striking examples of conformational
regulation occurs in the serpin family of protease inhibitors. Serpins fold into an active
structure that is unstable with respect to a second conformation. Interaction with target
protease triggers a conformational change, into the more stable structure. We are studying
the structure of several serpins, plasminogen activator inhibitor-1 (PAI-1), the primary
inhibitor of tissue plasminogen activator, CRM-A, an apoptosis regulator, and serpins from
tobacco hornworm, which serve as a model serpins. Recently, we have crystallized a complex
between a serpin and its target protease, the first complex to be studied
crystallographically. These studies are aimed at understanding the conformational changes
and the specificity of this important class of protease inhibitors.
Selected Publications:
Farley FW, Satterberg B, Goldsmith EJ and Elion EA (1999)
Relative Dependence of Different Outputs of the Saccharomyces cerevisiae Pheromone
Response Pathway on the MAP Kinase Fus3p. Genet. 151:1425-1444.
Gum RJ, McLaughlin MM, Kumar S, Wang Z, Bower MJ, Lee JC,
Adams JL, Livi JP, Goldsmith EJ and Young PR (1998) Acquisition of Sensitivity of
Stress-activated Protein Kinases to the p38 Inhibitor, SB203580, by Alteration of One or
More Amino Acids within the ATP Binding Pocket. J. Biol. Chem, 273:15605-15610.
Jinping Li, Wang Z, Canagarajah B, Jiang H, Kanost M and
Goldsmith EJ (1999) The Structure of Active Serpin K from Manduca sexta and A Model for
Serpin-Protease Complex Formation. Structure 7:103-109.
Wang Z, Canagarajah B, Boehm JC, Kassis S, Cobb MH, Young
PR, Abdel-Meguid S, Adams JL and Goldsmith EJ (1998) Structural Basis of MAP Kinase
Selectivity. Structure 6:1117-1128
A. V. Khokhlatchev, B. Canagarajah, J. Wilsbacher, M.
Robinson, M. Atkinson, E. J. Goldsmith and M. H. Cobb (1998) Phosphorylation of the map
kinase ERK2 promotes its homodimerization and nuclear translocation. Cell
93:605-615.
Canagarajah B, Khokhlatchev A, Cobb MH and Goldsmith EJ
(1997) The structure of phosphorylated MAP kinase ERK2 at 2.5 A resolution. Cell
90:859-869
Wang Z, Harkins PC, Ulevitch RJ, Han J, Cobb MH and
Goldsmith EJ (1997) The structure of the MAP kinase p38 and 2.1 A resolution. Proc Natl
Acad Sci USA 94:2327-2332
Goldsmith EJ (1996) Allosteric enzymes as models for
chemomechanical energy transducing assemblies. FASEB J 10:702-708
Goldsmith EJ and Cobb MH (1994) Protein kinases. Current
opinion in Structural Biology 4:833 840
Zhang F, Strand A, Robbins D, Cobb MH and Goldsmith EJ
(1994) Atomic structure of the MAP kinase ERK2 at 2.3 A resolution. Nature
367:704-711
Mottonen J, Strand A, Gerard RD, Symersky J, Geoghegan KF
and Goldsmith EJ (1992) Structural basis of latency in plasminogen activator inhibitor-1. Nature
355:270-273
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Last updated: 17 Jan 2002
Extraction Method: Expand using Medical Synonyms-
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