I am a structural biologist interested in how proteins are regulated by conformational changes, and have made significant contributions over the years to the analysis of protein kinases. Protein kinases represent a diverse set of molecular machines, carrying out precise programs of binding events, conformational changes and chemistry, often in a cascade. Our work has primarily focused on MAP kinase modules, and recently we have begun to study another short cascade comprised of the kinases WNK and OSR1/SPAK. These enzymes are medically important. Further, WNK1 itself is a salt sensor, a process that there is almost no data on. We are currently studying how WNK is regulated by salt or chloride, and how salt effects are transmitted into the next conformational step, which is breaking interactions with an autoinhibitory domain in WNK1. Our goal is a complete picture of the mechanism of the cascade. A secondary goal of my work is to learn enough about the mechanism of action of protein kinases to identify novel approaches toward drug discovery.
Over the past few years, my laboratory has significantly expanded the repertoire of biophysical methods we are using. We are using rt-PCR machine to do differential scanning fluorimetry (DSF) to find inhibitors of one of the kinases we are studying, TAO2. We have in press a paper on using TROSY NMR spectroscopy to observe conformational changes in the p38 MAP kinase, work done collaboratively with Kevin Gardner. We also have a Thermofinnigan mass spectrometer being used to determine phosphorylation order in MAP kinase modules.
In early work in this lab we also studied the serpin family of protease inhibitors, which undergo very interesting irreversible energy driven conformational changes (folding initially into a configuration that is not the most stable available to the polypeptide).
- University of California UCLA (1967), Chemistry
- Graduate School
- University of California UCLA (1971), Physical Chemistry
- Conformation regulation of protein molecules
- Protein kinases, how regulated, how inhibited
- Chloride Sensing by WNK1 Involves Inhibition of Autophosphorylation.
- Piala AT, Moon TM, Akella R, He H, Cobb MH, Goldsmith EJ Sci Signal 2014 7 324 ra41
- Precisely Ordered Phosphorylation Reactions in the p38 MAP Kinase Cascade.
- Humphreys JM, Piala AT, Akella R, He H, Goldsmith EJ J. Biol. Chem. 2013 Jun
- Solution Structure of the WNK1 Autoinhibitory Domain, a WNK-Specific PF2 Domain.
- Moon TM, Correa F, Kinch LN, Piala AT, Gardner KH, Goldsmith EJ J. Mol. Biol. 2013 Jan
- Three-dimensional docking in the MAPK p38a.
- Goldsmith EJ Sci Signal 2011 Dec 4 204 pe47
- The third conformation of p38a MAP kinase observed in phosphorylated p38a and in solution.
- Akella R, Min X, Wu Q, Gardner KH, Goldsmith EJ Structure 2010 Dec 18 12 1571-8
- Structural studies of MAP Kinase cascade components.
- Goldsmith EJ, Min X, He H, Zhou T Methods Mol. Biol. 2010 661 223-37
- Crystal structure of domain-swapped STE20 OSR1 kinase domain.
- Lee SJ, Cobb MH, Goldsmith EJ Protein Sci. 2009 Feb 18 2 304-13
- The structure of the MAP2K MEK6 reveals an autoinhibitory dimer.
- Min X, Akella R, He H, Humphreys JM, Tsutakawa SE, Lee SJ, Tainer JA, Cobb MH, Goldsmith EJ Structure 2009 Jan 17 1 96-104
- Natural language query in the biochemistry and molecular biology domains based on cognition search™.
- Goldsmith EJ, Mendiratta S, Akella R, Dahlgren K Summit on Translat Bioinforma 2009 2009 32-7
- Substrate and docking interactions in serine/threonine protein kinases.
- Goldsmith EJ, Akella R, Min X, Zhou T, Humphreys JM Chem. Rev. 2007 Nov 107 11 5065-81
Honors & Awards
- Patti L. Brown (Chilton) Professor of Biochemistry
Endowed Professorship (2011)
Postdoctoral Fellowship (1973)
Graduate Woman of the Year (1971)
Honors in Chemistry (1967)
- American Crystallographic Association
- Biophysical Society
- Protein Society