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Biochemistry Department - Primary Faculty

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

van den Akker Lab Website link

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 antibiotic resistance related proteins (such as bacterial beta-lactamases, penicillin binding proteins, and lytic transglycosylases) to cell signaling proteins such as guanylyl cyclases (for blood pressure, vision, and bone growth). Our lab employs state of the art multi-disciplinary biophysical, biochemical, crystallographic, computational, screening, 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 lytic transglycosylase from Campylobacter jejuni, a doughnut-shaped protein that degrades peptidoglycan (Click for coordinates or viewer) Collaboration with Jun Lin (U. of Tennessee).

Infectious diseases
Fighting antibiotic resistance (Click for coordinates or viewer) Collaboration with clinician researchers, biochemistists, microbiologists, and pharmaceutical industry; a new diazabicyclooctane beta-lactamase inhibitor

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 main focus in the van den Akker lab is on the molecular basis of antibiotic resistance. The projects entail the structure-function studies of bacterial enzymes involved in the metabolism of the peptidoglycan, a key bacterial drug target. We are investigating how bacteria become resistant to antibiotics/inhibitors targeting the peptidoglycan, as well as develop novel compounds. 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. In addition, we employ Molecular Dynamics simulations and fragment-based screening efforts to gain new insights and develop tool compounds. 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, Carey, Buynak, Prati, Lin, Mobashery, Papp-Wallace, and others).

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.

Additional collaborations. We have additional crystallographic and/or in silico drug screening collaborations with the labs of Sam Mesiano, Arne Rietsch, Jonathan Stamler, Dennis Stuehr, David Buchner, David Wald. In addition, we collaborate and receive funding from five pharmaceutical companies.

Selected References

  • Vijayaraghavan, J., Kumar, V., Krishnan, N.P., Kaufhold, R.T., Zeng, X., Lin, J., van den Akker, F.
    “ Structural studies and molecular dynamics simulations suggest a processive mechanism of exolytic lytic transglycosylase from Campylobacter jejuni. ”
    Plos One 2018, e0197136. Read article in PubMed
  • Papp-Wallace, K.M.*, Nguyen, N.Q., Jacobs, M.R., Bethel, C.R., Barnes, M.D., Kumar, V., Bajaksouzian, S., Rudin, S.D., Bhavsar, S., Ravikumar, T., Deshpande, P.K., Patil, V., Yeole, R., Bhagwat, S.S., Patel, M.V., van den Akker, F.*, Bonomo, R.A.*
    “ Strategic approaches to overcome resistance against Gram negative pathogens using beta-lactamase inhibitors and beta-lactam enhancers: The activity of three novel diazabicyclooctanes, zidebactam (WCK 5107), WCK 5153, WCK 4234. ”
    J. Med. Chem 2018, 61, 4067-4086. Read article in PubMed
  • van den Akker, F.*, Bonomo, R.A.
    “ Exploring additional dimensions of complexity in inhibitor design for serine beta-lactamases: mechanistic and intra- and inter-moleculra chemistry approach. ”
    Front Microbiol. 2018, 9, 622. Read article in PubMed
  • Chen A., Tiosano, D., Guran, T., Baris, H.N., Bayram, Y., Mory, A., Shapiro-Kulnane, L., Hodges, C.A., Coban Akdemir, Z., Turan, S., Jhangiani, S.N., van den Akker, F., Hoppel, C.L., Salz, H.K., Lupski, J.R., Buchner, D.A.
    “ Mutations in the mitochondrial ribosomal protein MRPS22 lead to primary ovarian insufficiency. ”
    Hum Mol. Genet. 2018, 27, 1913-1926. Read article in PubMed
  • Nguyen N.Q., Krishnan N.P., Rojas L.J., Prati F., Caselli E., Romagnoli C., Bonomo R.A., van den Akker F.
    “ Crystal structures of KPC-2 and SHV-1 beta-lactamases in complex with the boronic acid transition state analog S02030. ”
    Antimicrob Agents Chemother. 2016, 60, 1760-6. Read article in PubMed
  • Krishnan N.P., Nguyen N.Q., Papp-Wallace K.M., Bonomo R.A., van den Akker F.
    “ Inhibition of Klebsiella beta-Lactamases (SHV-1 and KPC-2) by Avibactam: A Structural Study. ”
    Plos One Sep 4;10(9):e0136813 (2015) Read article in PubMed
  • Rodkey E.A., Winkler, M.L., Bethel C.R., Pagadala, S.R.R., Buynak, J.D., Bonomo R.A., van den Akker F.
    “Penam sulfones and beta-lactamase inhibition: SA2-13 and the importance of the C2 side chain length and composition. ”
    Plos One Jan 16;9(1):e85892 (2014) Read article in PubMed
  • Rodkey E.A., McLeod D.C., Bethel C.R., Smith K.M., Xu Y., Chai W., Che T., Carey P.R., Bonomo R.A., van den Akker F., Buynak J.D.
    “beta-Lactamase Inhibition by 7-Alkylidenecephalosporin Sulfones: Allylic Transposition and Formation of an Unprecedented Stabilized Acyl-Enzyme. ”
    J. Am. Chem. Soc. Epub Dec 3(2013) Read article in PubMed
  • von Wantoch Rekowski M., Kumar V., Zhou Z., Moschner J., Marazioti A., Bantzi M., Spyroulias G.A., van den Akker F., Giannis A., Papapetropoulos A.
    “Insights into Soluble Guanylyl Cyclase Activation Derived from Improved Heme-Mimetics. ”
    J. Med. Chem. Epub Oct 24(2013) Read article in PubMed
  • 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
  • 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

 

Focco van den Akker Faculty's publications at pubmed