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.

LAB's STRUCTURES WITH PHARMACEUTICAL RELEVANCE

Cardiovascular diseases
A cool heme-mimetic at work! (Click for coordinates or viewer) Collaboration with BAYER HEALTHCARE; cinaciguat is in clinical trials for acute decompensated heart failure

The NO gaseous signaling molecule (Click for coordinates or viewer) Collaboration with cell biologist; nitric oxide is clinically used to treat primary pulmonary hypertension in neonatal patients

Infectious diseases
Fighting antibiotic resistance (Click for coordinates or viewer) Collaboration with clinician researchers, medicinal chemists, and spectroscopists; the clinical inhibitor tazobactam has an annual sales of around 1 billion dollars

Trying to improve existing drugs (Click for coordinates or viewer) Collaboration with clinician researchers, medicinal chemists, and spectroscopists; structure-based designed tazobactam analog with improved inhibitor intermediate properties

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, NO and BAY58-2667/cinaciguat 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 and involves a pre-clinical collaboration with pharmaceutical industry.
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. Our structure-based drug design efforts to combat antibiotic resistance involves clinician researchers, a medicinal chemist team, and structural biologists as well as pharmaceutical industry connections (this project is in collaboration with Drs. Bonomo, Skalweit (formerly Helfand), Carey, and Buynak).

Selected References

• Kumar V., Martin F.E., Hahn M.G., Schaefer M., Stamler J.S., Stasch J.P., van den Akker F.
  “Insights into BAY 60-2770 activation and S-nitrosylation-dependent desensitization of soluble guanylyl cyclase via crystal structures of homologous Nostoc H-NOX domain complexes. .”
  Biochemistry Epub Apr 24 (2013) Read article in PubMed
• Ke W., Pattanaik P., Bethel C.R., Sheri A., Buynak J.D., Bonomo R.A., van den Akker F.
  “Structures of SHV-1 beta-lactamase with penem and penam sulfone inhibitors that form cyclic intermediates stabilized by carbonyl conjugation.”
  Plos One e49035 (2012) Read article in PubMed
• Rodkey E.A., Drawz S.M., Sampson J.M. Bethel C.R., Bonomo R.A., and van den Akker F.
  “Crystal structure of a pre-acylation complex of the beta-lactamase inhibitor, sulbactam, bound to a sulfenamide bond containing thiol-beta-lactamase ”
  J. Am. Chem. Soc. epub Sep 26, (2012) Read article in PubMed
• Ke W., Laurent A.H., Armstrong M.D., Chen Y., Smith W.E., Liang J., Wright C.M., Ostermeier M., and van den Akker F.
  “Structure of an Engineered beta-Lactamase Maltose Binding Protein Fusion Protein: Insights into Heterotropic Allosteric Regulation ”
  Plos One 7: e39168 (2012) Read article in PubMed
• Ke W, Rodkey R.A., Sampson J.M., Skalweit M.J., Sheri A., Pagadala S.R.R., Nottingham M.D., Buynak J.D., Bonomo R.A., van den Akker F.
  “The importance of the trans-enamine intermediate as a beta-lactamase inhibition strategy probed in inhibitor-resistant SHV beta-lactamase variants”
  ChemMedChem 7: 1002-1008 (2012) Read article in PubMed
• Ke W., Bethel C.R., Papp-Wallace K.M., Pagadala S.R., Nottingham M., Fernandez D., Buynak J.D., Bonomo R.A., van den Akker F.
  “Crystal structures of KPC-2 beta-lactamase in complex with 3-NPBA and PSR-3-226”
  Antimicrob Agents Chemother ePub Feb 13 (2012) Read article in PubMedCentral
• Sampson J. M., Ke, W., Bethel, C. R., Pagadala, S. R. R., Nottingham, M. D., Bonomo R. A., Buynak, J. D., and van den Akker F.
  “Ligand dependent disorder of the omega loop observed in extended-spectrum SHV-type beta-lactamases”
  Antimicrob Agents Chemother 55 (1): 2303-2309 (2011). Read article in PubMedCentral
• Ke W., Sampson J. M., Ori C., Prati F., Drawz S. M., Bethel C. R., Bonomo R. A., and van den Akker F.
  “Novel insights into the mode of inhibition of class A SHV-1 beta-lactamases revealed by boronic acid transition state inhibitors”
  Antimicrob Agents Chemother 55 (1): 174-83 (2011). Read article in PubMedCentral
• Ma X., Beuve A., and van den Akker F.
  “Crystal structure of the signaling helix coiled-coil domain of the beta1 subunit of the soluble guanylyl cyclase”
  BMC Struct Biol 10: 2 (2010). Read article in PubMedCentral
• Martin F., Baskaran P., Ma X., Dunten P. W., Schaefer M., Stasch J. P., Beuve A., and van den Akker F.
  “Structure of cinaciguat (BAY 58-2667) bound to Nostoc H-NOX domain reveals insights into heme-mimetic activation of the soluble guanylyl cyclase”
  J Biol Chem 285 (29): 22651-7 (2010). Read article in PubMedCentral
• 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., Pagadala S. R., van den Akker F., Buynak J. D., and Bonomo R. A.
  “Strategic design of an effective beta-lactamase inhibitor: LN-1-255, a 6-alkylidene-2'-substituted penicillin sulfone”
  J Biol Chem 284 (2): 945-53 (2009). Read article in PubMedCentral
• Ma X., Sayed N., Baskaran P., Beuve A., and van den Akker F.
  “PAS-mediated dimerization of soluble guanylyl cyclase revealed by signal transduction histidine kinase domain crystal structure”
  J Biol Chem 283 (2): 1167-78 (2008). Read article in PubMedCentral
• Ma X., Sayed N., Beuve A., and van den Akker F.
  “NO and CO differentially activate soluble guanylyl cyclase via a heme pivot-bend mechanism”
  EMBO J 26 (2): 578-88 (2007). Read article in PubMedCentral
• Sayed N., Baskaran P., Ma X., van den Akker F., and Beuve A.
  “Desensitization of soluble guanylyl cyclase, the NO receptor, by S-nitrosylation”
  Proc Natl Acad Sci U S A 104 (30): 12312-7 (2007). Read article in PubMedCentral
• 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., and 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 (40): 13235-42 (2006). Read article in PubMedCentral