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case western reserve university

BIOCHEMISTRY
 
 

Dr. Focco van den Akker

Associate Professor

Pub Med:

Dr. Focco van den Akker

Multi-facetted structural approach to understanding the molecular signal transduction events of membrane receptors important for blood pressure regulation and bone growth, and proteins involved in antibiotic resistance

van den Akker Lab Web Page

A majority of today's medicines act via membrane bound receptors. These receptors are the communication portals for cells with mostly signals going into the cell but sometimes also signaling from the inside-out. Our lab is mainly focusing on the natriuretic peptide receptors and the nitric oxide (NO) regulated soluble guanylyl cyclase receptor which are wonderful complex signal transduction systems to tackle scientifically. These receptors are guanylyl cyclase receptors involved in processes such as blood pressure regulation and bone growth and their activation leads to the production of the intracellular second messenger cGMP. Deciphering the molecular signaling intricacies for these receptors is our paramount focus using a battery of approaches such as protein crystallography, cell biology, biochemical, biophysical, and computational ligand design techniques.

The van den Akker lab also studies beta-lactamases that are responsible for antibiotic resistance. A novel X-ray/Raman crystallography approach is employed and combined with rational drug design. By studing clinically important beta-lactamase inhibitors and their modes of inhibition, a novel beta-lactamase inhibitor was designed, synthesized, and observed to yield improved stabilization of a key intermediate. .

Selected References

  • Pattanaik, P., Bethel, C.R., Hujer, A.M., Hujer, K.M., Distler, A.M., Taracila, M., Anderson, V.E., Fritsche, T.R., Jones, R.N., Ram Reddy Pagadala, S., van den Akker, F., Buynak, J.D., Bonomo, R.A. Strategic design of an effective beta -lactamase Inhibitor: LN-1-255, a 6-alkylidene-2'-substituted penicillin sulfone (2008). J. Biol. Chem. In press (E-pub 10/27/08)

  • 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 (2008) J. Biol. Chem. 283, 1167-1178

  • Sayed, N., Baskaran, P., Ma, X., van den Akker, F., Beuve, A. Desensitization of soluble guanylyl cyclase, the NO-receptor, by S-nitrosylation (2007). PNAS 104, 12312-12317.

  • 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 b-lactamases (2007) Biochemistry 46, 5732-5740.

  • Ma, X., Sayed, N., Beuve, A., & van den Akker, F. NO and CO differentially activate soluble guanylyl cyclase via a heme pivot-bend mechanism (2007). EMBO J. 26, 578-588.

  • 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 (2006). J. Am. Chem. Soc. 128, 13235-13242.

  • Totir, M.A., Padayatti, P.S., Helfand, M.S., Carey M.P., Bonomo, R.A., Carey, P.R., & van den Akker, F. Effect of the Inhibitor-Resistant M69V Substitution on the Structures and Populations of trans-Enamine beta-Lactamase Intermediates (2006). Biochemistry 45, 11895-11904.

  • Padayatti, P.S. Helfand , M.S., Totir, M.A., Carey, M.P., Carey,P.R., Bonomo, R.A., & van den Akker, F. High resolution crystal structures of the trans-enamine intermediates formed by sulbactam and clavulanic acid and E166A SHV-1 b-lactamase (2005). J. Biol. Chem. 280, 34900-34907.

  • Padayatti, P.S., Pattanaik, P., Ma, X., van den Akker, F. Structural insights into the regulation and the activation mechanism of guanylyl cyclases (2004). Pharm. Therapeutics. 104, 83-99.

  • Bartels, C.F., Bukulmez, H., Padayatti, P., Rhee, D.K., Van Ravenswaaij-Arts, C., Pauli, R.M., Mundlos, S., Chitayat, D., Shih, L.Y., Al-Gazali, L.I., Kant, S., Cole, T., Morton, J., Cormier-Daire, V., Faivre, L., Lees, M., Kirk, J., Mortier, G.R., Leroy, J., Zabel, B., Kim, C.A., Crow, Y., Braverman, N.E., van den Akker, F., Warman, M.L. Mutations in the Transmembrane Natriuretic Peptide Receptor NPR-B Impair Skeletal Growth and Cause Acromesomelic Dysplasia, Type Maroteaux (2004). Am. J. Hum. Genet. 75, 27-34.

  • Padayatti, P.S., Helfand , M.S., Totir, M.A., Carey, M.P., Hujer, H.M., Carey,P.R., Bonomo, R.A., & van den Akker, F. Tazobactam forms a stoichiometric trans-enamine intermediate in the E166A variant of SHV-1 beta-lactamase: 1.63 Å crystal structure (2004). Biochemistry, 43, 843-848.

  • van den Akker, F. Structural insights into the ligand binding domains of membrane bound guanylyl cyclases and natriuretic peptide receptors (2001). J. Mol. Biol. 311, 923-937.

  • van den Akker, F., Zhang, X., Masaru, M., Huo, X., Misono, K.S., Yee, V.C. (2000) Crystal structure of the dimerized hormone binding domain of a guanylyl cyclase coupled receptor. Nature, 406, 101-104.

  • Chatterjee-Kishore, M., van den Akker, F., Stark, G.R. Association of STATs with relatives and friends (2000). Trends in Cell Biology 10, 106-111.

  • van den Akker, F. & Hol, W.G.J. (1999) Difference density quality (DDQ): A method to assess the global and local correctness of macromolecular crystal structures. Acta Cryst. D55, 206-218.