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Metal-Substituted Protein MRI Contrast Agents Engineered for Enhanced Relaxivity and Ligand Sensitivity

Lelyveld, Victor S. and Brustad, Eric and Arnold, Frances H. and Jasanoff, Alan (2011) Metal-Substituted Protein MRI Contrast Agents Engineered for Enhanced Relaxivity and Ligand Sensitivity. Journal of the American Chemical Society, 133 (4). pp. 649-651. ISSN 0002-7863. PMCID PMC3154012. doi:10.1021/ja107936d.

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Engineered metalloproteins constitute a flexible new class of analyte-sensitive molecular imaging agents detectable by magnetic resonance imaging (MRI), but their contrast effects are generally weaker than synthetic agents. To augment the proton relaxivity of agents derived from the heme domain of cytochrome P450 BM3 (BM3h), we formed manganese(III)-containing proteins that have higher electron spin than their native ferric iron counterparts. Metal substitution was achieved by coexpressing BM3h variants with the bacterial heme transporter ChuA in Escherichia coli and supplementing the growth medium with Mn^(3+)-protoporphyrin IX. Manganic BM3h variants exhibited up to 2.6-fold higher T_1 relaxivities relative to native BM3h at 4.7 T. Application of ChuA-mediated porphyrin substitution to a collection of thermostable chimeric P450 domains resulted in a stable, high-relaxivity BM3h derivative displaying a 63% relaxivity change upon binding of arachidonic acid, a natural ligand for the P450 enzyme and an important component of biological signaling pathways. This work demonstrates that protein-based MRI sensors with robust ligand sensitivity may be created with ease by including metal substitution among the toolkit of methods available to the protein engineer.

Item Type:Article
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URLURL TypeDescription DOIArticle CentralArticle
Arnold, Frances H.0000-0002-4027-364X
Jasanoff, Alan0000-0002-2834-6359
Additional Information:© 2010 American Chemical Society. Received: September 02, 2010. Article ASAP December 20, 2010. Published In Issue February 02, 2011. We thank Joseph Frank and L. Henry Bryant for help with NMRD measurements and Mikhail Shapiro and Fay Bi for helpful discussions. This work was supported by NIH Grant R01-DA28299 to A.J. and a Caltech Jacobs Grant to F.H.A. E.B. was supported by an NIH NRSA Fellowship (Award F32- GM087102).
Funding AgencyGrant Number
Jacobs Institute for Molecular Engineering for MedicineUNSPECIFIED
NIH Predoctoral FellowshipF32-GM087102
Issue or Number:4
PubMed Central ID:PMC3154012
Record Number:CaltechAUTHORS:20110322-095840300
Persistent URL:
Official Citation:Metal-Substituted Protein MRI Contrast Agents Engineered for Enhanced Relaxivity and Ligand Sensitivity Victor S. Lelyveld, Eric Brustad, Frances H. Arnold, Alan Jasanoff Journal of the American Chemical Society 2011 133 (4), 649-651
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:23046
Deposited By: Tony Diaz
Deposited On:22 Mar 2011 21:25
Last Modified:09 Nov 2021 16:10

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