Structure-activity relationships for the binding of polymyxins with human alpha-1-acid glycoprotein

Azad, Mohammad A. K., Huang, Johnny X., Cooper, Matthew A., Roberts, Kade D., Thompson, Philip E., Nation, Roger L., Li, Jian and Velkov, Tony (2012) Structure-activity relationships for the binding of polymyxins with human alpha-1-acid glycoprotein. Biochemical Pharmacology, 84 3: 278-291. doi:10.1016/j.bcp.2012.05.004

Author Azad, Mohammad A. K.
Huang, Johnny X.
Cooper, Matthew A.
Roberts, Kade D.
Thompson, Philip E.
Nation, Roger L.
Li, Jian
Velkov, Tony
Title Structure-activity relationships for the binding of polymyxins with human alpha-1-acid glycoprotein
Formatted title
Structure–activity relationships for the binding of polymyxins with human α-1-acid glycoprotein
Journal name Biochemical Pharmacology   Check publisher's open access policy
ISSN 0006-2952
Publication date 2012-08-01
Sub-type Article (original research)
DOI 10.1016/j.bcp.2012.05.004
Volume 84
Issue 3
Start page 278
End page 291
Total pages 14
Place of publication Philadelphia, PA, United States
Publisher Elsevier
Collection year 2013
Language eng
Formatted abstract
Here, for the first time, we have characterized binding properties of the polymyxin class of antibiotics for human α-1-acid glycoprotein (AGP) using a combination of biophysical techniques. The binding affinity of colistin, polymyxin B, polymyxin B3, colistin methansulfonate, and colistin nona-peptide was determined by isothermal titration calorimetry (ITC), surface plasma resonance (SPR) and fluorometric assay methods. All assay techniques indicated colistin, polymyxin B and polymyxin B3 display a moderate binding affinity for AGP. ITC and SPR showed there was no detectable binding affinity for colistin methansulfonate and colistin nona-peptide, suggesting both the positive charges of the diaminobutyric acid (Dab) side chains and the N-terminal fatty acyl chain of the polymyxin molecule are required to drive binding to AGP. In addition, the ITC and fluorometric data suggested that endogenous lipidic substances bound to AGP provide part of the polymyxin binding surface. A molecular model of the polymyxin B3–AGP F1*S complex was presented that illustrates the pivotal role of the N-terminal fatty acyl chain and the D-Phe6-L-Leu7 hydrophobic motif of polymyxin B3 for binding to the cleft-like ligand binding cavity of AGP F1*S variant. The model conforms with the entropy driven binding interaction characterized by ITC which suggests hydrophobic interactions coupled to desolvation events and conformational changes are the primary driving force for polymyxins binding to AGP. Collectively, the data are consistent with a role of this acute-phase reactant protein in the transport of polymyxins in plasma.
Keyword Human alpha-1-acid glycoprotein
Binding affinity
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
Institute for Molecular Bioscience - Publications
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