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Publication Citation: Effects of Desialylation on Human alpha1-Acid Glycoprotein-Ligand Interactions

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Author(s): Richard Y. Huang; Jeffrey W. Hudgens;
Title: Effects of Desialylation on Human alpha1-Acid Glycoprotein-Ligand Interactions
Published: September 16, 2013
Abstract: Human α1-Acid Glycoprotein (AGP), an acute phase glycoprotein, exists predominantly in blood. With its ability to bind basic, lipophilic, and acidic drugs, AGP has served as a drug carrier. It has been shown that the carbohydrate composition of AGP changes in response to tissue injury, inflammation or infection, and can have great impact on AGP's drug-binding activities. The molecular-level details of the effects of desialylation on the AGP conformation and AGP-ligand interactions, however, are unknown. Here we report the use of hydrogen/deuterium exchange coupled with mass spectrometry (HDX-MS) to reveal the changes in AGP conformational dynamics induced by the removal of terminal sialic acid. HDX-MS also reveals the changes in conformational dynamics of sialylated and unsialylated AGP upon formation of holo-AGP-complexes with progesterone or propranolol. Our HDX-MS results demonstrate that desialylation stabilizes two loop regions that are exterior to the β-sheet barrel in AGP, and this stabilization minimizes the conformational changes of AGP upon binding with progesterone or propranolol.
Citation: Biochemistry
Volume: 52
Issue: 40
Pages: pp. 7127 - 7136
Keywords: AGP, glycoprotein, human alpha1-acid, hydrogen/deuterium exchange, mass spectrometry, sialylation, progesterone, propranolol, HDX-ETD
Research Areas: Biological Product Characterization, Drugs/Pharmaceuticals, Protocols, Biomanufacturing, Mass
DOI: http://dx.doi.org/10.1021/bi4011094  (Note: May link to a non-U.S. Government webpage)
PDF version: PDF Document Click here to retrieve PDF version of paper (4MB)