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
Bowman, Sarah E J; Bridwell-Rabb, Jennifer; Drennan, Catherine L (2016) Metalloprotein Crystallography: More than a Structure. Acc Chem Res 49:695-702
Wittenborn, Elizabeth C; Jost, Marco; Wei, Yifeng et al. (2016) Structure of the Catalytic Domain of the Class I Polyhydroxybutyrate Synthase from Cupriavidus necator. J Biol Chem 291:25264-25277
Meyer, Peter A; Socias, Stephanie; Key, Jason et al. (2016) Data publication with the structural biology data grid supports live analysis. Nat Commun 7:10882
Gibson, Marcus I; Chen, Percival Yang-Ting; Johnson, Aileen C et al. (2016) One-carbon chemistry of oxalate oxidoreductase captured by X-ray crystallography. Proc Natl Acad Sci U S A 113:320-5
Jost, Marco; Born, David A; Cracan, Valentin et al. (2015) Structural Basis for Substrate Specificity in Adenosylcobalamin-dependent Isobutyryl-CoA Mutase and Related Acyl-CoA Mutases. J Biol Chem 290:26882-98
Jost, Marco; Fernández-Zapata, Jésus; Polanco, María Carmen et al. (2015) Structural basis for gene regulation by a B12-dependent photoreceptor. Nature 526:536-41
Jost, Marco; Simpson, Jeffrey H; Drennan, Catherine L (2015) The Transcription Factor CarH Safeguards Use of Adenosylcobalamin as a Light Sensor by Altering the Photolysis Products. Biochemistry 54:3231-4
Chang, Shiou-chi; Fedeles, Bogdan I; Wu, Jie et al. (2015) Next-generation sequencing reveals the biological significance of the N(2),3-ethenoguanine lesion in vivo. Nucleic Acids Res 43:5489-500
Gagnon, Derek M; Brophy, Megan Brunjes; Bowman, Sarah E J et al. (2015) Manganese binding properties of human calprotectin under conditions of high and low calcium: X-ray crystallographic and advanced electron paramagnetic resonance spectroscopic analysis. J Am Chem Soc 137:3004-16
Jost, Marco; Cracan, Valentin; Hubbard, Paul A et al. (2015) Visualization of a radical B12 enzyme with its G-protein chaperone. Proc Natl Acad Sci U S A 112:2419-24

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