Mechanism of action of cyclophilin A explored by metadynamics simulations
Mechanism of action of cyclophilin A explored by metadynamics simulations
复制标题
通过元动力学模拟探索亲环蛋白 A 的作用机制
DOI：
10.1016/j.bpj.2008.12.2266
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发表时间：
2009
影响因子：
3.4
通讯作者：
Leone V
中科院分区：
文献类型：
--
作者：
Leone V
PTEN是在多种人类肿瘤细胞中突变的肿瘤抑制因子。它通过使肌醇环3位的PI（3，4，5）P3去磷酸化来拮抗PI 3 K信号传导途径，并在细胞生长、增殖、存活和运动中起重要作用。3-脱氧-PI衍生物通过被认为涉及降低Akt 1磷酸化的机制对各种人类癌细胞系具有细胞毒性活性。然而，这些分子可以作为PTEN的抑制剂。合成了一系列D-3-脱氧-PI衍生物及其对映体（3-脱氧-diC 8 PI、3，5-脱氧-diC 8 PI和diC 8 PI），并研究了它们作为PTEN催化PI（3）P底物水解的抑制剂。在diC 8 PI（3）P作为底物的情况下，L-对映异构体通常不如D-化合物那样好的抑制剂，尽管随着脱氧的增加，效力增加。短链脂质在测定溶液中作为主要单体但具有一些小胶束的混合物存在。通过使用D-diC 16 PI（3）P作为底物，还检查了底物的聚集状态的影响。当底物在具有TX-100的胶束中呈现给PTEN时，3-脱氧-PI衍生物都不是良好的抑制剂。然而，当底物存在于大单层囊泡中时，3-脱氧-PI衍生物的抑制行为与在diC 8 PI（3）P单体/胶束系统中观察到的相似。还使用FRET研究了在脱氧-PI类似物存在下PTEN与PI囊泡的结合行为。结果表明，对于L-系列，肌醇头基上的脱氧增加了增强蛋白质与囊泡结合的效力。在这种情况下，L-3，5-双脱氧-diC 8 PI可以在较低浓度下增强结合50%，而L-diC 8 PI只能在大于ImM的高浓度下增强结合。这些结果用于评估PTEN中的脂质结合位点。2274-Pos Board B244激肽释放酶-激肽系统在鼻乳头状瘤和外源性鼻窦炎免疫应答中的作用Nurali Q. Botir B. Mahmudov 2. 1撒马尔罕州立大学，撒马尔罕，乌兹别克斯坦; 2撒马尔罕国立医学研究所，撒马尔罕，乌兹别克斯坦。本研究旨在探讨激肽释放酶-激肽系统的酶活性与良性鼻乳头状瘤和鼻窦炎免疫应答激活之间的可能联系。本文对64例鼻乳头状瘤和鼻窦炎患者及20例正常人进行了激肽释放酶-激肽系统酶活性、细胞免疫和体液免疫的检测。用血清或血浆样品研究激肽释放酶-激肽系统的酶活性和抗体反应。通过T淋巴细胞、B淋巴细胞和O淋巴细胞的分析来评价细胞免疫应答。激肽释放酶活性和细胞免疫应答的比较分析表明，激肽释放酶活性的升高与T淋巴细胞的活化具有良好的相关性（r 0. 05）。896)和T-抑制子（rº0. 975），表明激肽释放酶的活性在调节T细胞应答中可能是重要的。相反，激肽释放酶-激肽系统的激活与B淋巴细胞的诱导无关（r 0. 05）。578），T辅助细胞（rº0. 694)O-淋巴细胞（r 0. 569）。在同一研究组中，对激肽释放酶活性和体液免疫应答的分析表明，激肽释放酶-激肽系统的诱导与伊加的显著升高相关（r 0. 785），与较低水平的IgG和IgM表达相反。B淋巴细胞指数与激肽酶活性呈高度正相关（r 0. 05）。768 …
PTEN is a tumor suppressor mutated in a large variety of human tumor cells. It antagonizes the PI3K signaling pathway by dephosphorylating the PI (3, 4, 5) P3 at the 3 position of the inositol ring and plays an important role in cell growth, proliferation, survival and motility. 3-Deoxy-PI derivatives have cytotoxic activity against various human cancer cell lines by a mechanism thought to involve reduced Akt1 phosphorylation. However, these molecules could act as inhibitors of PTEN. A series of D-3-deoxy-PI derivatives and their enantiomers (3-deoxy-diC8PI, 3, 5-dideoxy-diC8PI and diC8PI) had been synthesized and studied as inhibitors of PTEN catalyzed hydrolysis of PI (3) P substrates. With diC8PI (3) P as the substrate, the L-enantiomers are usually not as good inhibitors as the D-compounds, although there is an increase in potency with increasing deoxygenation. The short-chain lipids exist in the assay solution as a mix of mostly monomers but with some small micelles. By using D-diC16PI (3) P as the substrates, the effect of the aggregation state of the substrates was also checked. When the substrates are presented to PTEN in micelles with TX-100, none of the 3-deoxy-PI derivatives are good inhibitors. However, when the substrates are presented in large unilamellar vesicles, the inhibitory behavior of the 3-deoxy-PI derivatives is similar to what was observed in the diC8PI (3) P monomer/micelle system. The binding behavior of PTEN to PI vesicles in the presence of the deoxy-PI analogs has also been studied using FRET. The results showed that for the L-series, deoxygenation on the inositol head group increases the potency of enhancing the protein binding to the vesicles. In this case, L-3, 5-dideoxy-diC8PI can enhance binding by 50% at the lower concentration, while L-diC8PI can only enhance binding at the high concentration larger than 1mM. These results are used to assess lipid binding sites in PTEN.2274-Pos Board B244 The role of Kallikrein-kinin System in the Immune Response of Nasal Papilloma and Adventitious Sinusitis Nurali Q. Muhamadiev1, Botir B. Mahmudov2. 1Samarkand State University, Samarkand, Uzbekistan, 2Samarkand State Medical Institute, Samarkand, Uzbekistan. The work was dedicated to study the possible interconnection between the enzymatic activity of kallikrein-kinin system and the activation of immune response of benign nasal papilloma and adventitious sinusitis. 64 patients with nasal papilloma and adventitious sinusitis have been examined for the enzymatic activity of kallikrein-kinin system and for the cellular and humoral immune responses, as well as 20 healthy. The enzymatic activity of kallikrein-kinin system and antibody response were investigated by using the sera or plasma samples. Cellular immune response was evaluated by analyzing of T-lymphocytes, B-lymphocytes and O-lymphocytes. Comparative analysis of kallikrein activity and cellular immune response showed that elevation of kallikrein activity was well correlated with activation of T-lymphocytes (rº0. 896) and T-supressors (rº0. 975), indicating that the activity of kallikrein may be important in modulation of T-cell response. In contrast, activation of kallikrein-kinin system was not associated with induction of B-lymphocytes (rº0. 578), T-helpers (rº0. 694) and O-lymphocytes (rº0. 569). Analysis of kallikrein activity and humoral immune response in the same study group showed that induction of kallikrein-kinin system was associated with substantial elevation of IgA (rº0. 785), in contrast to lower level of IgG and IgM expression. It is also revealed that there is a high correlation between kininase activity and the indices of B-lymphocytes (rº0. 768 …