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Molecular Mechanisms of Tight Binding through Fuzzy Interactions
Shen, Qingliang,Shi, Jie,Zeng, Danyun,Zhao, Baoyu,Li, Pingwei,Hwang, Wonmuk,Cho, Jae-Hyun Elsevier 2018 Biophysical journal Vol.114 No.6
<P><B>Abstract</B></P> <P>Many intrinsically disordered proteins (IDPs) form fuzzy complexes upon binding to their targets. Although many IDPs are weakly bound in fuzzy complexes, some IDPs form high-affinity complexes. One example is the nonstructural protein 1 (NS1) of the 1918 Spanish influenza A virus, which hijacks cellular CRKII through the strong binding affinity (K<SUB>d</SUB> ∼10 nM) of its proline-rich motif (PRM<SUP>NS1</SUP>) to the N-terminal Src-homology 3 domain of CRKII. However, its molecular mechanism remains elusive. Here, we examine the interplay between structural disorder of a bound PRM<SUP>NS1</SUP> and its long-range electrostatic interactions. Using x-ray crystallography and NMR spectroscopy, we found that PRM<SUP>NS1</SUP> retains substantial conformational flexibility in the bound state. Moreover, molecular dynamics simulations showed that structural disorder of the bound PRM<SUP>NS1</SUP> increases the number of electrostatic interactions and decreases the mean distances between the positively charged residues in PRM<SUP>NS1</SUP> and the acidic residues in the N-terminal Src-homology 3 domain. These results are analyzed using a polyelectrostatic model. Our results provide an insight into the molecular recognition mechanism for a high-affinity fuzzy complex.</P>
Surface Modification with Pluronic P123 Enhances Transfection Efficiency of PAMAM Dendrimer
Xiang Wang,Shen Gao,Xin Wu,Wei Fan,Baoyue Ding,Xiaoyu Wang,Wei Zhang,Xueying Ding,Jing Gao,Quangang Zhu,Jiyong Liu,Zhen Cai 한국고분자학회 2012 Macromolecular Research Vol.20 No.2
To improve gene delivery efficiency and decrease cytotoxicity of polyamidoamine (PAMAM) polymers,P123-g-PAMAM was synthesized by modifying PAMAM with pluronic P123. The structure of the synthesized polymers was analyzed using proton nuclear magnetic resonance. The polymers were able to self-assemble with DNA,forming nanometer-scale complexes. Particle size measurement confirmed that the mean diameter of the polyplexes was 100-250 nm. The cytotoxicity and transfer efficiency were measured and compared with those of PEI and PAMAM. All of the polyplexes showed significantly low cytotoxicity in the MCF-7, HepG2, and 293T cell lines. In addition, the low level of P123 grafting to PAMAM showed significantly higher transfection efficiency than unmodified PAMAM at the optimal N/P ratio. These results suggest that P123-ylated PAMAM may prove as a useful carrier for gene delivery.
Genmeng Yang,Juan Li,Yanxia Peng,Baoyu Shen,Yuanyuan Li,Liu Liu,Chan Wang,Yue Xu,Shucheng Lin,Shuwei Zhang,Yi Tan,Huijie Zhang,Xiaofeng Zeng,Qi Li,Gang Lu 고려인삼학회 2022 Journal of Ginseng Research Vol.46 No.3
This study investigates the effects of ginsenoside Rb1 (GsRb1) on methamphetamine (METH)-induced toxicity in SH-SY5Y neuroblastoma cells and METH-induced conditioned place preference (CPP)in adult Sprague-Dawley rats. It also examines whether GsRb1 can regulate these effects through theNR2B/ERK/CREB/BDNF signaling pathways. Methods: SH-SY5Y cells were pretreated with GsRb1 (20 mM and 40 mM) for 1 h, followed by METHtreatment (2 mM) for 24 h. Rats were treated with METH (2 mg/kg) or saline on alternating days for 10days to allow CPP to be examined. GsRb1 (5, 10, and 20 mg/kg) was injected intraperitoneally 1 h beforeMETH or saline. Western blot was used to examine the protein expression of NR2B, ERK, P-ERK, CREB, PCREB, and BDNF in the SH-SY5Y cells and the rats' hippocampus, nucleus accumbens (NAc), and prefrontal cortex (PFC). Results: METH dose-dependently reduced the viability of SH-SY5Y cells. Pretreatment of cells with 40mM of GsRb1 increased cell viability and reduced the expression of METH-induced NR2B, p-ERK, p-CREBand BDNF. GsRb1 also attenuated the expression of METH CPP in a dose-dependent manner in rats. Further, GsRb1 dose-dependently reduced the expression of METH-induced NR2B, p-ERK, p-CREB, andBDNF in the PFC, hippocampus, and NAc of rats. Conclusion: GsRb1 regulated METH-induced neurotoxicity in vitro and METH-induced CPP through theNR2B/ERK/CREB/BDNF regulatory pathway. GsRb1 could be a therapeutic target for treating METHinduced neurotoxicity or METH addiction.