About Us

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We work on problems that are interesting from multiple perspectives. Protein kinases are regulated in interesting ways and are drug targets. We use screening to find inhibitors. We use crystallography, biochemical assays, mutagenesis, and mass spectrometry to study regulation autophosphorylation. Dr. Melanie Cobb, Ph.D. who is a pioneer in the MAP kinase field, has been the source of many of our kinase targets including With No Lysine (K) (WNK) kinases 1-5, TAO kinases 6-7, and MAP kinase pathway components 8-10. We collaborate with the chemist, Uttam Tambar, and a nephrologist, Aylin Rodan.

Important earlier work from the Goldsmith lab concerns the development of an second generation protein drug (tPA)11, crystallographic studies of the very interesting serpin family of protease inhibitors 12, crystallography of MAP kinase pathway components 13-15.

  1. Akella, R.; Drozdz, M. A.; Humphreys, J. M.; Jiou, J.; Durbacz, M. Z.; Mohammed, Z. J.; He, H.; Liwocha, J.; Sekulski, K.; Goldsmith, E. J., A Phosphorylated Intermediate in the Activation of WNK Kinases. Biochemistry 2020, 59 (18), 1747-1755.
  2. Akella, R.; Sekulski, K.; Pleinis, J. M.; Liwocha, J.; Jiou, J.; He, H.; Humphreys, J. M.; Schlessinger, J. N.; Joachimiak, A.; Rodan, A. R.; Goldsmith, E. J., Anatomy of a Pressure Sensing Protein Kinase. bioRxiv 2018.
  3. Sun, Q.; Wu, Y.; Jonusaite, S.; Pleinis, J. M.; Humphreys, J. M.; He, H.; Schellinger, J. N.; Akella, R.; Stenesen, D.; Kramer, H.; Goldsmith, E. J.; Rodan, A. R., Intracellular Chloride and Scaffold Protein Mo25 Cooperatively Regulate Transepithelial Ion Transport through WNK Signaling in the Malpighian Tubule. J Am Soc Nephrol 2018.
  4. Piala, A. T.; Moon, T. M.; Akella, R.; He, H.; Cobb, M. H.; Goldsmith, E. J., Chloride sensing by WNK1 involves inhibition of autophosphorylation. Sci Signal 2014, 7 (324), ra41.
  5. Min, X. S.; Lee, B. H.; Cobb, M. H.; Goldsmith, E. J., Crystal structure of the kinase domain of WNK1, a kinase that causes a hereditary form of hypertension. Structure 2004, 12 (7), 1303-1311.
  6. Piala, A. T.; Potts, M. B.; Posner, B. A.; Goldsmith, E. J., Discovery of novel TAOK2 Inhibitor Scaffolds from High Throughput Screening. Bioorg Med Chem Lett 2016, in press.
  7. Zhou, T.; Raman, M.; Gao, Y.; Earnest, S.; Chen, Z.; Machius, M.; Cobb, M. H.; Goldsmith, E. J., Crystal structure of the TAO2 kinase domain: activation and specificity of a Ste20p MAP3K. Structure 2004, 12 (10), 1891-900.
  8. Jindal, G. A.; Goyal, Y.; Humphreys, J. M.; Yeung, E.; Tian, K.; Patterson, V. L.; He, H.; Burdine, R. D.; Goldsmith, E. J.; Shvartsman, S. Y., How activating mutations affect MEK1 regulation and function. J Biol Chem 2017, 292 (46), 18814-18820.
  9. Min, X.; Akella, R.; He, H.; Humphreys, J. M.; Tsutakawa, S. E.; Lee, S. J.; Tainer, J. A.; Cobb, M. H.; Goldsmith, E. J., The structure of the MAP2K MEK6 reveals an autoinhibitory dimer. Structure 2009, 17 (1), 96-104.
  10. Humphreys, J. M.; Piala, A. T.; Akella, R.; He, H.; Goldsmith, E. J., Precisely ordered phosphorylation reactions in the p38 mitogen-activated protein (MAP) kinase cascade. Journal of Biological Chemistry 2013, 288 (32), 23322--23330.
  11. Madison, E. L.; Goldsmith, E. J.; Gerard, R. D.; Gething, M. J.; Sambrook, J. F., Serpin-resistant mutants of human tissue-type plasminogen activator. Nature 1989, 339 (6227), 721-4.
  12. Mottonen, J.; Strand, A.; Symersky, J.; Sweet, R. M.; Danley, D. E.; Geoghegan, K. F.; Gerard, R. D.; Goldsmith, E. J., Structural basis of latency in plasminogen activator inhibitor-1. Nature 1992, 355 (6357), 270-3.
  13. Zhang, F.; Strand, A.; Robbins, D.; Cobb, M. H.; Goldsmith, E. J., Atomic structure of the MAP kinase ERK2 at 2.3 A resolution. Nature 1994, 367 (6465), 704-11.
  14. Canagarajah, B. J.; Khokhlatchev, A.; Cobb, M. H.; Goldsmith, E. J., Activation mechanism of the MAP kinase ERK2 by dual phosphorylation. Cell 1997, 90 (5), 859-69.
  15. Chang, C. I.; Xu, B. E.; Akella, R.; Cobb, M. H.; Goldsmith, E. J., Crystal structures of MAP kinase p38 complexed to the docking sites on its nuclear substrate MEF2A and activator MKK3b. Mol Cell 2002, 9 (6), 1241-9.