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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.|
|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:||Click here to retrieve PDF version of paper (4MB)|