Document Type
Article
Publication Date
8-31-2012
Department
Biological Sciences
School
Biological, Environmental, and Earth Sciences
Abstract
Macrophage migration inhibitory factor (MIF) is a catalytic cytokine and an upstream mediator of the inflammatory pathway. MIF has broad regulatory properties, dysregulation of which has been implicated in the pathology of multiple immunological diseases. Inhibition of MIF activity with small molecules has proven beneficial in a number of disease models. Known small molecule MIF inhibitors typically bind in the tautomerase site of the MIF trimer, often covalently modifying the catalytic proline. Allosteric MIF inhibitors, particularly those that associate with the protein by noncovalent interactions, could reveal novel ways to block MIF activity for therapeutic benefit and serve as chemical probes to elucidate the structural basis for the diverse regulatory properties of MIF. In this study, we report the identification and functional characterization of a novel allosteric MIF inhibitor. Identified from a high throughput screening effort, this sulfonated azo compound termed p425 strongly inhibited the ability of MIF to tautomerize 4-hydroxyphenyl pyruvate. Furthermore, p425 blocked the interaction of MIF with its receptor, CD74, and interfered with the pro-inflammatory activities of the cytokine. Structural studies revealed a unique mode of binding for p425, with a single molecule of the inhibitor occupying the interface of two MIF trimers. The inhibitor binds MIF mainly on the protein surface through hydrophobic interactions that are stabilized by hydrogen bonding with four highly specific residues from three different monomers. The mode of p425 binding reveals a unique way to block the activity of the cytokine for potential therapeutic benefit in MIF-associated diseases.
Publication Title
Journal of Biological Chemistry
Volume
287
Issue
36
First Page
30653
Last Page
30663
Recommended Citation
Bai, F.,
Asojo, O. A.,
Cirillo, P.,
Ciustea, M.,
Ledzidet, M.,
Aristoff, P. A.,
Leng, L.,
Koski, R. A.,
Powell, T. J.,
Bucala, R.,
Anthony, K. G.
(2012). A Novel Allosteric Inhibitor of Macrophage Migration Inhibitory Factor (MIF). Journal of Biological Chemistry, 287(36), 30653-30663.
Available at: https://aquila.usm.edu/fac_pubs/154
Comments
This research was originally published in Journal of Biological Chemistry. Bai, Fengwei. "A Novel Allosteric Inhibitor of Macrophage Migration Inhibitory Factor (MIF)." Journal of Biological Chemistry.2012; 287:30653-30663. © the American Society for Biochemistry and Molecular Biology. http://www.jbc.org/content/287/36/30653.full.pdf+html