Case Western Reserve University

Focco van den Akker, Ph.D.

Associate Professor

Education

• Ph.D.: University of Washington, Seattle
• Postdoc: with George R. Stark at Lerner Research Institute, Cleveland Clinic

Research Interests

The overall goal of my research is to elucidate the molecular intricacies of enzyme mechanism and receptor activation and using that knowledge to develop inhibitors and activators for pharmaceutical purposes. Our projects range from cell signaling proteins such as guanylyl cyclases (blood pressure, vision, and bone growth) to beta-lactamases (responsible for the current epidemic antibiotic resistance). Our lab employs state of the art multi-disciplinary biophysical, biochemical, crystallographic, molecular biology, and cell biology techniques.
The guanylyl cyclases can be either membrane bound or soluble and are activated by either peptides or nitric oxide (NO), respectively. Our lab has recently published on new insights regarding the dimerization and NO activation of the soluble guanylyl cyclase. Our structural studies are also aimed at developing new activators to treat cardiovascular diseases such as heart-failure, hypertension, erectile dysfunction, and atherosclerosis.
The beta-lactamase project entails the structure-function studies of these enzymes and investigating their modes of becoming resistant to antibiotics and inhibitors. We employ a novel synergistic Raman/X-ray crystallographic approach to allowed detailed time-dependence and structural information of intermediate formation of inhibitors and antibiotics. We have used this information to improve inhibition aspects of clinical and novel inhibitors via the rational drug design cycle (in collaboration with Drs. Bonomo, Helfand, Carey, and Buynak).

Selected References

• Ma, X., Sayed, N., Beuve, A., & van den Akker, F.
  “PAS-like dimerization of soluble guanylyl cyclase revealed by signal transduction histidine kinase domain structure.”
  J. Biol. Chem. 283, 1167-1178 (2008).
• Ma, X., Sayed, N., Beuve, A., & van den Akker, F.
  “NO and CO differentially activate soluble guanylyl cyclase via a heme pivot-bend mechanism”
  EMBO J. 26, 578-588 (2007).
• Ke, K., Bethel, C.R., Thomson, J.M., Bonomo, R.A., van den Akker, F.
  “Crystal structure of KPC-2: Insights into carbapenemase activity in class A beta-lactamases.”
  Biochemistry 46, 5732-5740 (2007).
• Padayatti, P.S., Sheri, A., Totir, M.A., Helfand, M.S. Carey, M.P., Anderson, V.E., Carey,P.R., Bethel, C.R., Bonomo, R.A., Buynak, J.D. & van den Akker, F.
  “Rational design of a beta-lactamase inhibitor achieved via stabilization of the trans-enamine intermediate: 1.28 A crystal structure of wt SHV-1 complex with a penam sulfone.”
  J. Am. Chem. Soc. 128, 13235-13242 (2006).
• van den Akker, F., Zhang, X., Masaru, M., Huo, X., Misono, K.S., Yee, V.C.
  “Crystal structure of the dimerized hormone binding domain of a guanylyl cyclase coupled receptor.”
  Nature 406, 101-104 (2000).