Structure-activity relationships for the binding of polymyxins with human α-1-acid glycoprotein.
Structure-activity relationships for the binding of polymyxins with human α-1-acid glycoprotein.
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DOI：
10.1016/j.bcp.2012.05.004
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发表时间：
2012-08-01
影响因子：
5.8
通讯作者：
Velkov, Tony
中科院分区：
文献类型：
--
作者：
Azad, Mohammad A. K.;Huang, Johnny X.;Cooper, Matthew A.;Roberts, Kade D.;Thompson, Philip E.;Nation, Roger L.;Li, Jian;Velkov, Tony
本研究首次结合生物物理技术表征了多粘菌素类抗生素与人α-1-酸性糖蛋白（AGP）的结合特性。采用等温滴定量热法（ITC）、表面等离子体共振法（SPR）和荧光法测定粘菌素、多粘菌素B、多粘菌素B3、粘菌素甲磺酸盐和多粘菌素nona肽的结合亲和力。所有检测技术表明粘菌素、多粘菌素B和多粘菌素B3对AGP具有中等的结合亲和力。ITC和SPR结果显示，多粘菌素与甲磺酸粘菌素和多粘菌素nona肽的结合亲和力均未检测到，提示多粘菌素分子的二氨基丁酸（Dab）侧链和n端脂肪酰基链的正电荷都需要驱动与AGP的结合。此外，ITC和荧光数据表明，与AGP结合的内源性脂质物质提供了部分多粘菌素结合表面。本文建立了多粘菌素B3 - AGP F1*S复合物的分子模型，揭示了多粘菌素B3的n端脂肪酰基链和D-Phe6-L-Leu7疏水基序在AGP F1*S变体的裂隙状配体结合腔中的关键作用。该模型符合ITC特征的熵驱动结合相互作用，表明疏水相互作用耦合脱溶事件和构象变化是多粘菌素与AGP结合的主要驱动力。总的来说，这些数据与这种急性期反应蛋白在血浆中多粘菌素运输中的作用是一致的。
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.
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影响因子：
11.4
作者：
DENTE, L;PIZZA, MG;CORTESE, R
通讯作者：
CORTESE, R
影响因子：
4.9
作者：
DUDLEY, MN;BLASER, J;ZINNER, SH
通讯作者：
ZINNER, SH
影响因子：
10.5
作者：
DENTE, L;RUTHER, U;CORTESE, R
通讯作者：
CORTESE, R
DOI：
10.1016/0378-4347(93)80289-g
发表时间：
1993-05-19
期刊：
JOURNAL OF CHROMATOGRAPHY-BIOMEDICAL APPLICATIONS
影响因子：
--
作者：
HERVE, F;GOMAS, E;TILLEMENT, JP
通讯作者：
TILLEMENT, JP
DOI：
10.1097/00008571-199610000-00004
发表时间：
1996-10-01
期刊：
PHARMACOGENETICS
影响因子：
--
作者：
Herve, F;Duche, JC;Tillement, JP
通讯作者：
Tillement, JP