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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM069857-08
Application #
8286294
Study Section
Macromolecular Structure and Function A Study Section (MSFA)
Program Officer
Smith, Ward
Project Start
2004-01-02
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
8
Fiscal Year
2012
Total Cost
$266,511
Indirect Cost
$86,540
Name
Massachusetts Institute of Technology
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139
Kung, Yan; Ando, Nozomi; Doukov, Tzanko I et al. (2012) Visualizing molecular juggling within a B12-dependent methyltransferase complex. Nature 484:265-9
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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