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.
|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; FernÃ¡ndez-Zapata, JÃ©sus; Polanco, MarÃa 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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