Office: 843-792-1468
Lab: 843-792-1019
Fax: 843-792-8568
Email: davies@musc.edu
BSB-518D
click here for lab page

Research Interests

Understanding the function of a macromolecule involved in a particular biological process often requires knowledge of its precise three-dimensional structure. This is especially relevant in cases where the molecule has a role in disease. Our group uses the technique of X-ray crystallography, as well as other biochemical approaches, to determine high-resolution structures of macromolecules in a variety of systems. The primary focus of the laboratory is to decipher the structure and function of enzymes involved in peptidoglycan synthesis in bacteria. These include penicillin-binding proteins (PBPs), the well-known molecular targets for ß-lactam antibiotics. Due to the prevalence of antibiotic resistance in bacteria, which poses an increasing threat to public health, these enzymes are of considerable interest. We have recently determined the structure and catalytic mechanism of PBP 5 from E. coli and are now using this system as a vehicle to develop novel antimicrobials directed against pathogenic bacteria. In tandem, we are elucidating many of the molecular mechanisms that underlie antibiotic resistance in Neisseria gonorrhoeae by determining the structures of key proteins involved. The long-term goals of this work are to (a) design new inhibitors against PBPs and (b) via structure determination and biochemical investigation, to develop new molecular targets for antimicrobials.

Selected Publications

• Huang, Y., Fedarovich, A., Tomlinson, S. & Davies, C (2007). Crystal structure of CD59: implications for molecular recognition of the complement proteins C8 and C9 in the membrane-attack complex. Acta Crystallogr D Biol Crystallogr. 63: 714-721.
  
• Tsybovsky, Y. Donato, H., Krupenko, N.I.,Davies, C & Krupenko, S.A. (2007). Crystal structures of the carboxyl terminal domain of rat 10-formyltetrahydrofolate dehydrogenase: implications for the catalytic mechanism of aldehyde dehydrogenases. Biochem. 46, 2917-2929.
  
• Josephine, H.R., Charlier, P., Davies, C., Nicholas, R.A. & Pratt, R.F. (2006). Reactivity of penicillin-binding proteins with peptidoglycan-mimetic ß-lactams: What’s wrong with these enzymes? Biochem. 45: 15873-15883.
  
• Swan, M.K., Bastia , D. & Davies, C. (2006). Crystal structure of Pi initiator protein-iteron complex of plasmid R6K: Implications for initiation of plasmid DNA replication. Proc. Natl. Acad. Sci. USA 103: 18481-18486.
  
• Fedarovich, A., Tomberg, J., Nicholas, R.A. & Davies, C. (2006). Crystal structure of the N-terminal domain of human CEACAM1: binding target of the opacity proteins during invasion of Neisseria meningitidis and N. gonorrhoeae. Acta Cryst., D62: 971-979.
  
• Powell, A.J., Liu, Z-J., Nicholas, R.A. & Davies, C. (2006). Crystal structures of the lytic transglycosylase MltA from N. gonorrhoeae and E. coli: insights into interdomain movements and substrate binding. J. Mol. Biol. 359: 122-136.
  
• Hansen, T., Schlichting, B., Grötzinger, J., Swan, M.K., Davies, C. & Schönheit, P. (2005). Mutagenesis of catalytically important residues of cupin type phosphoglucose isomerase from Archaeoglobus fulgidus. FEBS J. 272: 6266-6275.
  
• Nicola, G., Fedarovich, A., Nicholas, R.A. & Davies, C. (2005). A large displacement of the SxN motif of Cys115-modified penicillin-binding protein 5 from E. coli. Biochem. J. 392: 55-63.
  
• Hu, M., Nandi, S., Davies, C. & Nicholas, R.A. (2005). High-level chromosomally mediated tetracycline resistance in Neisseria gonorrhoeae is due to a point mutation in ribosomal protein S10 (RpsJ) in combination with the mtrR and penB resistance determinants. Antimicrob. Agents Chemother. 49: 4327-4334.
  
• Nicola, G., Peddi, S., Stefanova, M., Nicholas, R.A., Gutheil, W.G. & Davies, C. (2005). Crystal structure of Escherichia coli penicillin-binding protein 5 bound to a tripeptide boronic acid inhibitor: a role for Ser110 in deacylation. Biochemistry 44: 8207-8217.
  
• Swan, M.K., Hansen, T., Schönheit, P. & Davies, C. (2004). The structural basis for phosphomannose isomerase activity in phosphoglucose isomerase from P. aerophilum: a subtle difference between distantly related enzymes. Biochemistry, 43: 14088-14095.
  
• Solomons, J.T.G., Zimmerly, E.M., Burns, S., Krishnamurthy, N., Swan, M.K., Krings, S., Muirhead, H., Chirgwin, J. & Davies, C. (2004). The crystal structure of mouse phosphoglucose isomerase at 1.6 Å resolution and its complex with glucose 6-phosphate reveals the catalytic mechanism of sugar ring opening. J. Mol. Biol., 342: 847-860.
  
• Swan, M.K., Hansen, T., Schönheit, P. & Davies, C. (2004). A novel phosphoglucose isomerase/phosphomannose isomerase from the crenarchaeon Pyrobaculum aerophilum is a member of the PGI superfamily: structural evidence at 1.16Å resolution. J. Biol. Chem.279: 39838-39845.
  
• Swan, M.K., Hansen, T., Schönheit, P. & Davies, C. (2004). Crystallisation and preliminary x-ray diffraction analysis of phosphoglucose/phosphomannose isomerase from Pyrobaculum aerophilum. Acta Cryst., D60: 1481-1483.
  
• Chumanevich, A.A., Krupenko , S.A. & Davies, C. (2004). The crystal structure of the hydrolase domain of 10-formyltetrahydrofolate dehydrogenase: mechanism of hydrolysis and its interplay with the dehydrogenase domain. J. Biol. Chem., 279: 14355-14364.
  
• Stefanova, M.E., Tomberg, J., Davies, C., Nicholas, R.A. & Gutheil, W.G. (2004) Overexpression and enzymatic characterization of Neisseria gonorrhoeae penicillin-binding protein 4. Eur. J. Biochem., 271: 23-32.
  
• Nicholas, R.A., Krings, S., Tomberg, J., Nicola, G. & Davies, C. (2003) Crystal structure of wild-type penicillin-binding protein 5 from E. coli:  Implications for deacylation of the acyl-enzyme complex. J. Biol. Chem. 278: 52826-52833.
  
• Swan, M.K., Solomons, J.T.G., Hansen, T., Schönheit, P. & Davies, C. (2003) Structural evidence for a hybride transfer mechanism of catalysis in phosphoglucose isomerase from Pyrococcus furiosus. J. Biol. Chem., 278: 47261-47268.
  
• Swan, M.K., Hansen, T., Schönheit, P. & Davies, C. (2003) Crystallization and preliminary x-ray diffraction analysis of phosphoglucose isomerase from Pyrococcus furiosus. Prot. Pept. Letts., 10: 517-520.
  
• Davies, C., Muirhead, H. & Chirgwin, J. (2003) The structure of human phosphoglucose isomerase complexed with a transition-state analogue. Acta Cryst., D59: 1111-1113.
  
• Davies, C. & Muirhead, H. (2003) The crystal structure of native phosphoglucose isomerase from rabbit:  conformational changes associated with catalytic function. Acta Cryst., D59: 453-465.
  
• Davies, C. & Muirhead, H. (2002) The crystal structure of pig phosphoglucose isomerase and its complex with 5-phosphoarabinonate. Prot. Struc. Fun. Gen., 49: 577-579.
  
• Chumanevich, A.C., Davies, C. & Krupenko, S.A. (2002) Crystallization and preliminary X-ray diffraction analysis of recombinant hydrolase domain of 10-formyltetrahydrofolate dehydrogenase. Acta Cryst., D58: 1841-1842.
  
• Stefanova, M.E., Davies, C., Nicholas, R.A. & Gutheil, W.G. (2002) pH, inhibitor and substrate specifcity studies on Escherichia coli Penicillin-Binding Protein 5. Biochim Biophys. Acta 1597: 292-300.
  
• Read, J., Pearce, J. Li, X., Muirhead, H., Chirgwin, J. & Davies, C. (2001). The crystal structure of human phosphoglucose isomerase at 1.6 Å resolution: implications for catalytic mechanism, cytokine activity and haemolytic anaemia. J. Mol. Biol. 309, 447-464.
  
• Davies, C., White, S.W., and Nicholas, R.A. (2001) Crystal structure of a deacylation-defective mutant of penicillin-binding protein 5 at 2.3 Å resolution. J. Biol. Chem. 276, 616-623.
  
• Caspari, T., Davies, C. and Carr, A.M. (2000). Analysis of the Fission Yeast Checkpoint Rad proteins. Cold Spring Harbour Symposium of Quantitative Biology. LXV, 451-456.
  
• Davies, C. and White, S.W. (2000) Electrons and X-rays gang up on the ribosome. Structure Fold. Des., 8, R41-45.
  
• Davies, C., Heath, R.J., White, S.W., and Rock, C.O. (2000) The 1.8 Å crystal structure and active site architecture of beta-ketoacyl-acyl carrier protein synthase III (FabH) from Escherichia coli. Structure Fold. Des. 8, 185-195.
  
• Davies, C., Bussiere, D.E., Golden, B.L., Porter, S.J., Ramakrishnan, V. and White, S.W. (1998) Ribosomal proteins S5 and L6: high resolution crystal structures and roles in protein synthesis and antibiotic resistance. J. Mol. Biol., 279, 873-888.
  
• Davies, C., Gerstner, R.B., Draper, D.E., Ramakrishnan, V. and White, S.W. (1998) The crystal structure of ribosomal protein S4 reveals a two-domain molecule with an extensive RNA-binding surface: one domain shows structural homology to the ETS DNA-binding motif. EMBO J., 16, 4545-4558.
  
• Kugler, W., Breme, K., Laspe, P., Muirhead, H., Davies, C., Winkler, H., Schroter, W., and Lakomek, M. (1998) Molecular basis of neurological dysfunction coupled with haemolytic anaemia in human glucose-6-phosphate isomerase (GPI) deficiency. Hum. Genet. 103, 450-454.
  
• Davies, D., Beauchamp, J., Emery, D., Rawas, A. and Muirhead, H. (1997) Crystal structure of the Fab fragment from a neutralizing monoclonal antibody directed against an epitope of gp41 from HIV-1. Acta Cryst., D53, 186-194.
  
• Manna, A.C., Pai, K.S., Bussiere, D.E., Davies, C., White, S.W. and Bastia, D. (1996) Helicase-contrahelicase interaction and the mechanism of termination of DNA replication. Cell, 87, 881-891.
  
• Davies, C., Ramakrishnan, V. and White, S.W. (1996) Structural evidence for specific S8-RNA and S8-protein interactions within the 30S ribosomal subunit - ribosomal protein S8 from Bacillus stearothermophilus at 1.9 Å. Structure, 4, 1093-1104.
  
• Davies, C., White, S.W. and Ramakrishnan, V. (1996) The crystal structure of ribosomal protein L14 reveals an important organizational component of the translational apparatus. Structure, 4, 55-66.