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 #
2R01GM069857-05A1
Application #
7736814
Study Section
Macromolecular Structure and Function A Study Section (MSFA)
Program Officer
Basavappa, Ravi
Project Start
2004-01-02
Project End
2013-06-30
Budget Start
2009-09-30
Budget End
2010-06-30
Support Year
5
Fiscal Year
2009
Total Cost
Indirect Cost
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
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Gibson, Marcus I; Chen, Percival Yang-Ting; Drennan, Catherine L (2016) A structural phylogeny for understanding 2-oxoacid oxidoreductase function. Curr Opin Struct Biol 41:54-61

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