The primary focus of my laboratory currently is structural studies of MAP kinase module components. MAP kinase module generate switch like responses through the catalysis of the two double phosphorylation reactions, and we would like understand this switch mechanism. We are learning that the dual specificity of the central MAP2Ks is associated with its phosphorylation status, and the enzyme has different activities as it becomes phosphorylated. Further, MAP kinase modules maintain pathway specificity, despite the similarity of MAP kinase components from one module to the next. We are learning that this is accomplished through a variety of autoinhibition schemes, and interaction induced conformational changes. We found for example that MAP2Ks form autoinhibited dimeric structures in the absence of substrates, and that the MAPKs have a special "Processing Conformation" in which its activation loop is exposed that is induced by docking interactions with kinases and phosphatases. These studies are part of a long-term collaboration with Dr. Melanie Cobb of the Pharmacology Department.
A second project in the laboratory is to augment existing Natural Language query software (Cognition Technologies, Santa Monica, CA) for the biomedical domain. Cognition carries out "concept search." The concept is what is fixed in the dictionary, but many words can point to that concept. Similarly, a word can point to several different concepts, and the desired meaning must be worked out from the context. The result is better precision-- you can find what you are actually looking for. Cognition also has tools for language acquisition, which we are using to capture synonymy and ontological relationships from web-based sources for biomedical terms. We have worked on protein names. The current state of this effort can presently be found at www.cognitionsearch.com/health which has Medline indexed with the dictionary we helping to improve. We plan to serve locally for UT Southwestern full text search of open source papers in the near future.
In Press in Chemical Reviews
Substrate Interactions of Ser/Thr Protein Kinases" E. J. Goldsmith, R. Akella, T. Zhou and J. Humphreys
Submitted for publication
An Excursion from Ser/Thr Kinase to Tyrosine Kinase Activity Underlies the Threshold Behavior of MAP Kinase Modules? John M. Humphreys, Seung-Jae Lee, Haixia He, Prashanti Madhavapeddi, Yue Chen, Yinming Zhao, and Elizabeth J. Goldsmith
RESEARCH INTERESTS
Conformation regulation of protein molecules
Enzyme specificity
Protein design
RECENT PUBLICATIONS
X. Min, Byung-Hoon Lee, Malanie H. Cobb, and Elizabeth J. Goldsmith, "Crystal Structure of the Kinase Domain of WNK1, a Kinase that Causes a Hereditary Form of Hypertension" Structure, 12:1303-1311, 2004
Chang, C., Xu, B., Akella, R., Cobb, M.H., and Goldsmith, E.J., "Crystal Structures of MAP Kinase p38 Complexed to the Docking Sites on Its Nuclear Substrate MEF2A and Activator MKK3b." Mol. Cell, 9:1241-1249, 2002
T. Zhou, Malavika Raman, Yan Gao, Zhu Chen, Mischa Machius, Melanie H. Cobb, and Elizabeth J. Goldsmith, "Active Structure of the TAO2 Kinase Domain: Activation and Specificity of a Ste20p MAP3K" Structure, 12:1891-900, 2004
Zhou, T, Sun, L, Humphreys, J, and Goldsmith, EJ, "Docking Interactions Induce Exposure of Activation Loop in the MAP Kinase ERK2" Structure, 6:1011-9, 2006
Zhou, T, Sun, LG, Gao Y, and Goldsmith, EJ, "Crystal Structure of the MAP3K TAO2 Kinase Domain Bound by an Inhibitor Staurosporine" Acta Biochim Biophys Sin (Shanghai), 6:385-92, 2006
SIGNIFICANT PUBLICATIONS
Goldsmith, E.J., "Allosteric enzymes as models for chemomechanical energy transducing assemblies." FASEB J., 10:702-703, 1996
Canagarajah, B., Khokhlatchev, A., Cobb, M.H., and Goldsmith, E.J., "The structure of phosphorylated MAP kinase ERK2 at 2.5 E resolution." Cell, 90:859-869, 1997
Ye, S., Cech, A., Belmares, R., Bergstrom, R., Corey, D., Kanost, M., and Goldsmith, E.J., "The structure of a Michaelis Serpin-Protease Complex." Nature Struct. Biol., 8:979-983, 2001
Chang, C., Xu, B., Akella, R., Cobb, M.H., and Goldsmith, E.J., "Crystal Structures of MAP Kinase p38 Complexed to the Docking Sites on Its Nuclear Substrate MEF2A and Activator MKK3b." Mol. Cell, 9:1241-1249, 2002
Cobb, M.H., and Goldsmith, E.J., "How MAP kinases are regulated." J. Biol. Chem., 270:14843-14846, 1995
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