Metal ions in biology allow for an expanded chemical repertoire;the local protein environment and metal coordination sphere act synergistically to confer unique reactivity. It is therefore not surprising that the reactions catalyzed by metalloenzymes are chemically challenging and essential for life. We use X-ray crystallography and computation to study the structure and mechanism of complex metallocofactors. Our findings have applications for the synthesis of biomimetic catalysts and in the design of enzyme inhibitors. In addition to interrogating the mechanisms of metalloenzymes, it is important to investigate the cellular regulation of trace mineral levels required for metallocenter assembly, as well as to study the assembly process itself. This proposal focuses on nickel and iron-sulfur containing proteins and their metallochaperones, as well as the regulation of nickel uptake and iron-sulfur cluster assembly.
The proposed research uses X-ray crystallography and computation as the chief tools to investigate nickel, iron-sulfur and corrinoid containing proteins, with a focus on proteins involved in one-carbon metabolism. Our goals are to explore the mechanism and assembly of complex metallocofactors, as well as the cellular regulation of nickel uptake and iron-sulfur cluster biogenesis.
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|Kung, Yan; Drennan, Catherine L (2011) A role for nickel-iron cofactors in biological carbon monoxide and carbon dioxide utilization. Curr Opin Chem Biol 15:276-83|
|Phillips, Christine M; Stultz, Collin M; Drennan, Catherine L (2010) Searching for the Nik operon: how a ligand-responsive transcription factor hunts for its DNA binding site. Biochemistry 49:7757-63|
|Phillips, Christine M; Schreiter, Eric R; Stultz, Collin M et al. (2010) Structural basis of low-affinity nickel binding to the nickel-responsive transcription factor NikR from Escherichia coli. Biochemistry 49:7830-8|
|Kung, Yan; Doukov, Tzanko I; Seravalli, Javier et al. (2009) Crystallographic snapshots of cyanide- and water-bound C-clusters from bifunctional carbon monoxide dehydrogenase/acetyl-CoA synthase. Biochemistry 48:7432-40|
|Blasiak, Leah C; Drennan, Catherine L (2009) Structural perspective on enzymatic halogenation. Acc Chem Res 42:147-55|
|Phillips, Christine M; Schreiter, Eric R; Guo, Yayi et al. (2008) Structural basis of the metal specificity for nickel regulatory protein NikR. Biochemistry 47:1938-46|
|Doukov, Tzanko I; Blasiak, Leah C; Seravalli, Javier et al. (2008) Xenon in and at the end of the tunnel of bifunctional carbon monoxide dehydrogenase/acetyl-CoA synthase. Biochemistry 47:3474-83|
|Frick, Lauren E; Delaney, James C; Wong, Cintyu et al. (2007) Alleviation of 1,N6-ethanoadenine genotoxicity by the Escherichia coli adaptive response protein AlkB. Proc Natl Acad Sci U S A 104:755-60|
|Schreiter, Eric R; Drennan, Catherine L (2007) Ribbon-helix-helix transcription factors: variations on a theme. Nat Rev Microbiol 5:710-20|
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