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.

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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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Macromolecular Structure and Function A Study Section (MSFA)
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Smith, Ward
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Massachusetts Institute of Technology
Schools of Arts and Sciences
United States
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Bridwell-Rabb, Jennifer; Drennan, Catherine L (2017) Vitamin B12 in the spotlight again. Curr Opin Chem Biol 37:63-70
Nakashige, Toshiki G; Zygiel, Emily M; Drennan, Catherine L et al. (2017) Nickel Sequestration by the Host-Defense Protein Human Calprotectin. J Am Chem Soc 139:8828-8836
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