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Paul Carey

Professor
Department of Biochemistry
School of Medicine

Research Information

Research Interests

Research in the Carey lab focuses on the development and application of Raman spectroscopy to probe the structure and dynamics of enzyme-substrate intermediates. Many studies involve following reactions in single protein and nucleic acid crystals, an approach termed Raman crystallography. Thus, compounds such as drug candidates can be infused into crystals and, by employing Raman difference spectroscopy, Raman data are obtained for the drug bound in the active site. Analysis of the data yields structural information that provides key insights into factors such as the molecular basis of drug resistance. A parallel approach on crystals of RNA ribozymes has shown that unique information can be obtained on the properties of active site groups and the chemistry of metal binding. Constant efforts are underway to “push the envelope” to extend the size and complexity of the systems under analysis. Recent experiments provide detailed, time-resolved data on the synthesis of a RNA dimer in a RNAPolymerase-DNA crystalline complex with a molecular weight in excess of 120,000 Daltons.

Publications

  • Carey P.R, Whitmer G.R, Yoon M.J, Lombardo M.N, Pusztai-Carey M., Heidari-Torkabadi H., Che T.
    “Measuring Drug-Induced Changes in Metabolite Populations of Live Bacteria: Real Time Analysis by Raman Spectroscopy”
    J Phys Chem B. 122 (24): 6377-6385 (2018).
  • Carey P.R, Gibson B.R., Gibson J.F., Greenberg M.E., Heidari-Torkabadi H., Pusztai-Carey M., Weaver S.T., Whitmer G.R.
    “Defining Molecular Details of the Chemistry of Biofilm Formation by Raman Microspectroscopy. ”
    Biochemistry 56(17): 2247-2250. (2017)
  • Heidari-Torkabadi H., Bethel C.R., Ding Z., Pusztai-Carey M., Bonnet R., Bonomo R.A., Carey P.R.
    “"Mind the Gap": Raman Evidence for Rapid Inactivation of CTX-M-9 β-Lactamase Using Mechanism-Based Inhibitors that Bridge the Active Site. ”
    J Am Chem Soc. 137(40):12760-3. (2015).
  • Carey P.R., Heidari-Torkabadi H.
    “New techniques in antibiotic discovery and resistance: Raman spectroscopy.”
    Ann N Y Acad Sci. 1354:67-81.(2015).
  • Antonopoulos IH, Warner BA, Carey PR.
    “Concerted Protein and Nucleic Acid Conformational Changes Observed Prior to Nucleotide Incorporation in a Bacterial RNA Polymerase: Raman Crystallographic Evidence. ”
    Biochemistry. 54(34):5297-305 (2015).
  • Heidari-Torkabadi H., Che T., Lombardo M.N., Wright D.L., Anderson A.C., Carey P.R.
    “Measuring propargyl-linked drug populations inside bacterial cells, and their interaction with a dihydrofolate reductase target, by Raman microscopy.”
    Biochemistry. 54(17):2719-26. (2015).
  • Antonopoulos I.H., Murayama Y., Warner B.A., Sekine S., Yokoyama S., Carey P.R.
    “Time-resolved Raman and polyacrylamide gel electrophoresis observations of nucleotide incorporation and misincorporation in RNA within a bacterial RNA polymerase crystal.”
    Biochemistry. 54(3):652-65.(2015).
  • Che T., Rodkey E.A., Bethel C.R., Shanmugam S., Ding Z., Pusztai-Carey M., Nottingham M., Chai W., Buynak J.D., Bonomo R.A., van den Akker F., Carey P.R.
    “Detecting a quasi-stable imine species on the reaction pathway of SHV-1 β-lactamase and 6β-(hydroxymethyl)penicillanic acid sulfone. ”
    Biochemistry. 54(3):734-43.(2015).
  • Heidari Torkabadi H., Bethel C.R., Papp-Wallace K.M., de Boer P.A., Bonomo R.A., Carey P.R.
    “Following drug uptake and reactions inside Escherichia coli cells by Raman microspectroscopy. ”
    Biochemistry. 53(25):4113-21. (2014).
  • Nottingham M., Bethel C. R., Pagadala S. R., Harry E., Pinto A., Lemons Z. A., Drawz S. M., Akker F., Carey P. R., Bonomo R. A., and Buynak J. D.
    “Modifications of the C6-substituent of penicillin sulfones with the goal of improving inhibitor recognition and efficacy”
    Bioorg Med Chem Lett 21 (1): 387-93 (2011).
  • Carey P. R., Chen Y., Gong B., and Kalp M.
    “Kinetic crystallography by Raman microscopy”
    Biochim Biophys Acta : (2010).
  • Chen Y., Eldho N. V., Dayie T. K., and Carey P. R.

    Biochemistry 49 (16): 3427-35 (2010). 
  • Gong B., Chen J. H., Yajima R., Chen Y., Chase E., Chadalavada D. M., Golden B. L., Carey P. R., and Bevilacqua P. C.

    Methods 49 (2): 101-11 (2009). 
  • Guo M., Spitale R. C., Volpini R., Krucinska J., Cristalli G., Carey P. R., and Wedekind J. E.

    J Am Chem Soc 131 (36): 12908-9 (2009). 
  • Kalp M., Bethel C. R., Bonomo R. A., and Carey P. R.

    Biochemistry 48 (41): 9912-20 (2009). 
  • Kalp, M., Totir, M. A., Buynak, J. D. and Carey, P. R.
    “Different Intermediate Populations Formed by Tazobactam, Sulbactam, and Clavulanate Reacting with SHV-1 ?-lactamase: Raman Crystallographic Evidence.”
    J Amer. Chem. Soc. 131, 2338-47, (2009).
  • Kalp, M., and Carey, P. R.
    “Carbapenems and SHV-1 ?-lactamase Form Different Acyl-Enzyme Populations in Crystals and Solution”
    Biochemistry 47, 11830-37, (2008).
  • Gong, B., Chen, Y. Y., Christian, E. L., Chen, J. H., Chase, E., Chadalavada, D. M., Yajima, R., Golden, B. L., Bevilacqua, P. C., and Carey, P. R.
    “Detection of Inner-sphere Interactions between Magnesium Hydrate and the Phosphate Backbone of the HDV Ribozyme Using Raman Crystallography”
    J. Am. Chem. Soc. 130: 9670-72, (2008).
  • Helfand M. S., Taracila M. A., Totir M. A., Bonomo R. A., Buynak J. D., van den Akker F., and Carey P. R.
    “Raman crystallographic studies of the intermediates formed by Ser130Gly SHV, a beta-lactamase that confers resistance to clinical inhibitors”
    Biochemistry 46 (29): 8689-99 (2007).
  • Gong, B., Chen, J.H., Chase, E., Chadalavada D.M., Yajima R., Golden B.L., Bevilacqua P.C., and Carey, P. R.
    “Direct measurement of pKa near neutrality for the catalytic cytosine in genomic HDV ribozyme using Raman crystallography”
    J. Amer. Chem. Soc. 129: 13335-13342, (2007).
  • Carey, P. R.
    “Raman Crystallography and Other Biochemical Applications of Raman Microscopy”
    Ann. Rev. Phys. Chem. 57: 527-554, (2006).
  • Hall P. R., Zheng R., Antony L., Pusztai-Carey M., Carey P. R., and Yee V. C.

    EMBO J 23 (18): 3621-31 (2004). 
  • Hall P. R., Zheng R., Pusztai-Carey M., van den Akker F., Carey P. R., and Yee V. C.
    “Expression and crystallization of several forms of the Propionibacterium shermanii transcarboxylase 5S subunit”
    Acta Crystallogr D Biol Crystallogr 60 (Pt 3): 521-3 (2004).

Education

Doctor of Philosophy
University of Sussex
Post Doc
National Research Council of Canada