The Drennan laboratory uses X-ray crystallography as the chief tool for investigating the structure and function of enzymes that are medically important or valuable in environmental remediation. We are particularly interested in metalloprotein biochemistry and in the role of conformational change in catalysis. Representative projects are described below.

Metalloenzymes & Medicine
Ribonucleotide reductases (RNRs) catalyze an essential step in DNA biosynthesis, the conversion of ribonucleotides to deoxyribonucleotides. RNR inhibition reduces cellular pools of deoxynucleoside triphosphates (dNTPs) and consequently impairs DNA biosynthesis and repair. As a result of these activities, RNRs are being pursued as targets for antiviral and antitumor therapies. To provide a molecular understanding of the catalytic and allosteric regulatory enzyme mechanisms, we are carrying out crystallographic studies of the simplest members of the RNR family (class II RNRs).

Metalloenzymes & the Environment
Carbon monoxide dehydrogenases (CODHs) play an important role in reducing levels of toxic CO gas in our environment. An estimated 108 tons of CO are removed annually from the earth and lower atmosphere by bacteria. A better understanding of the structure and mechanism of Ni-Fe-S-dependent carbon monoxide dehydrogenases could lead to development of biomimetic catalysts to lower CO levels in heavily polluted regions.

Metal Uptake & Metallocluster Assembly
Trace metals are essential for life. Organisms must obtain sufficient quantities of trace metals for growth, while also preventing the accumulation of excess metal that can be toxic to the cell. Our laboratory wants to understand the regulation of cellular metal uptake, and the cellular assembly of metallocofactors. We have begun our studies by investigating Ni uptake in E. coli, and Fe-S cluster assembly in Synechocystis.

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Phillips, C.M., Schreiter, E.R., Guo, Y., Wang, S.C., Zamble, D.B., and Drennan, C.L. (2008) Structural Basis of Metal Specificity for Nickel Regulatory Protein NikR, Biochemistry 47,1938-1946.

Ryan, K.S., Balibar, C.J., Turo, K.E., Walsh, C.T., and Drennan, C.L. (2008) The Violacein Biosynthetic Enzyme VioE Shares a Fold with Lipoprotein Transporter Proteins, Journal of Biological Chemistry 283, 6467-6475.

Doukov, T.I., Blasiak, L.C., Seravalli, J., Ragsdale, S.W., and Drennan, C.L. (2008) Xenon In and at the End of the Tunnel of Bifunctional Carbon Monoxide Dehydrogenase/Acetyl-CoA Synthase, Biochemistry 47, 3474-3483.

Ryan, K.S., Howard-Jones, A.R., Hamill, M.J., Elliott, S.J., Walsh, C.T., and Drennan, C.L., (2007) Crystallographic Trapping in the Rebeccamycin Biosynthetic Enzyme RebC, Proceedings of the National Academy of Science U.S.A. 104, 15311-15316.

Hubbard, P.A., Padovani, D., Labunska, T., Mahlstedt, S.A., Banerjee, R., and Drennan. C.L., (2007) Crystal Structure and Mutagensis of the Metallochaperone MeaB: Insight into the Causes of Methylmalonic Aciduria, Journal of Biological Chemistry 282, 31308-31316.

Frick, L.E., Delaney, J.C., Wong, C., Drennan, C.L., and Essigmann, J.M. (2007) Alleviation of 1,N6-Ethanoadenine Genotoxicity by the Escherichia coli Adaptive Response Protein AlkB, Proceedings of the National Academy of Science U.S.A. 104, 755-760.

Yeh, E., Blasiak, L.C., Koglin, A., Drennan, C.L., and Walsh, C.T. (2007) Chlorination by a Long-lived Intermediate in the Mechanism of Flavin-dependent Halogenases, Biochemistry 46, 1284-1292.

Doukov, T.I, Hemmi, H., Drennan, C.L., and Ragsdale, S.W.  (2007) Structural and Kinetic Evidence for an Extended Hydrogen Bonding Network in Catalysis of Methyl Group Transfer: Role of an Active Site Asparagine Residue in Activation of Methyl Transfer by Methyltransferases, Journal of Biological Chemistry 282, 6609-6618.

Chobot, S.E., Hernandez, H.H., Drennan, C.L., and Elliott, S.J., (2007) Direct Electrochemical Characterization of Archaeal Thioredoxins, Angewandte Chemie International Edition 46, 4145-4147.

Schreiter, E.R. and Drennan, C.L. (2007) Ribbon-Helix-Helix Transcription Factors: Variations on a Theme, Nature Reviews in Microbiology 5, 710–720.

Schreiter, E.R., Wang, S. C., Zamble, D.B., and Drennan, C.L. (2006) NikR-operator Complex Structure and the Mechanism of Repressor Activation by Metal Ions, Proceedings of the National Academy of Science U.S.A. 103, 13676-13681.

Blasiak, L.C., Vaillancourt, F.H., Walsh, C.T., Drennan, C.L. (2006) Crystal structure of the non-haem iron halogenase SyrB2 in syringomycin biosynthesis, Nature 440, 368-371.

Higgins, L. J., Yan, F., Liu P., Liu, H.-W., Drennan, C. L. (2005) Structural Insight into Antibiotic Fosfomycin Biosynthesis by a Mononuclear Iron Enzyme, Nature 437, 838–844.

Delaney, J.C., Smeester, L., Wong, C., Frick, L. E., Taghizadeh, L., Wishnok, J. S., Drennan, C. L., Samson, L. D., Essigmann, J. M. (2005) AlkB reverses etheno DNA lesions caused by lipid oxidation in vitro and in vivo, Nature Structural & Molecular Biology 12, 855-860.

Andrade, S. L. A., Cruz, F., Drennan, C. L., Ramakrishnan, V., Rees, D. C., Ferry, J. G., and Einsle, O. (2005) Structures of the Iron-Sulfur Flavoproteins from Methanosarcina thermophila and Archaeoglobus fulgidus, Journal of Bacteriology 187, 3848–3854.

Berkovitch, F., Nicolet, Y., Wan, J.T., Jarrett, J.T., and Drennan, C.L. (2004) The Crystal Structure of Biotin Synthase, an S-Adenosylmethionine-Dependent Radical Enzyme, Science 303, 76-79.

Berkovitch F., Behshad, E., Kuo-Hsiang Tang, K-H., Enns, E.A., Frey, P.A., and Drennan, C.L. (2004) A Locking Mechanism Preventing Radical Damage in the Absence of Substrate, as Revealed by the X-ray Structure of Lysine 5,6-Aminomutase, Proceedings of the National Academy of Science U.S.A. 101, 15870–15875.

Tirupati, B., Vey, J.L., Drennan, C.L., and Bollinger, J.M. Jr. (2004) Kinetic and Structural Characterization of Slr0077/SufS, the Essential Cysteine Desulfurase from Synechocystis sp. PCC 6803, Biochemistry 43, 12210–12219.

Nicolet, Y., and Drennan, C.L. (2004) AdoMet Radical Proteins – from Structure to Evolution – Alignment of Divergent Protein Sequences Reveals Strong Secondary Structure Element Conservation, Nucleic Acids Research 32, 4015–4025.

Midelfort, K.S., Hernandez, H.H., Lippow, S.M., Tidor, B., Drennan, C.L., and Wittrup, K.D. (2004) Substantial Energetic Improvement with Minimal Structural Perturbation in a High Affinity Mutant Antibody, Journal of Molecular Biology, 343, 685–701.

Drennan, C.L., Doukov, T.I., and Ragsdale, S.W. (2004) The Metalloclusters of Carbon Monoxide Dehydrogenase/Acetyl-CoA Synthase: A Story in Pictures, Journal of Biological Inorganic Chemistry 9, 511–515.

Schreiter, E.R., Sintchak, M.D., Guo, Y., Chivers, P.T., Sauer, R.T., and Drennan, C.L. (2003) Crystal Structure of the Nickel-Responsive Transcription Factor NikR, Nature Structural Biology 10, 794–799.

Drennan, C.L. and Peters, J.W. (2003) Surprising Cofactors in Metalloenzymes, Current Opinion in Structural Biology 13, 220–226.

Doukov, T.I., Iverson, T.M., Seravalli, J., Ragsdale, S.W., and Drennan, C.L. (2002) A Ni-Fe-Cu Center in a Bifunctional Carbon Monoxide Dehydrogenase/Acetyl-CoA Synthase, Science 298, 567–572.

Sintchak, M.D., Arjara, G., Kellogg, B.A., Stubbe, J., and Drennan, C.L. (2002) The Crystal Structure of Class II Ribonucleotide Reductase Reveals How an Allosterically Regulated Monomer Mimics a Dimer, Nature Structural Biology 9, 293–300.

Drennan, C.L., Heo, J., Sintchak, M.D., Schreiter, E., Ludden, P.W. (2001) Life on Carbon Monoxide: X-ray Structure of Rhodospirillum rubrum Ni-Fe-S Carbon Monoxide Dehydrogenase, Proceedings of the National Academy of Sciences U.S.A. 98, 11973–11978.

Marsh, E.N.G. and Drennan, C.L. (2001) Structure and Mechanism of the Adenosylcobalamin-dependent Isomerases, Current Opinion in Chemical Biology 5, 499–505.