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Crystal structure of an inactive Akt2 kinase domain   总被引:5,自引:0,他引:5  
Akt/PKB represents a subfamily of three isoforms from the AGC serine/threonine kinase family. Amplification of Akt activity has been implicated in diseases that involve inappropriate cell survival, including a number of human malignancies. The structure of an inactive and unliganded Akt2 kinase domain reveals several features that distinguish it from other kinases. Most of the alpha helix C is disordered. The activation loop in this structure adopts a conformation that appears to sterically hinder the binding of both ATP and peptide substrate. In addition, an intramolecular disulfide bond is observed between two cysteines in the activation loop. Residues within the linker region between the N- and C-terminal lobes also contribute to the inactive conformation by partially occupying the ATP binding site.  相似文献   
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Dear Editor,Globally,gastric cancer is the most common malignant tumor and the second highest contributor to cancer deaths after lung cancer(Murray et al.,2012).Despite improved success with treatment of early stage gastric cancer(Fuse et al.,2016),the five-year survival rate of advanced staged gastric cancer patients is still low.The aggressive growth characteristics of the tumor and metastasis are key factors responsible for poor overall survival in these patients(Ozkan et al.,2005).Therefore,investigation of the molecular mechanisms that underlie the aggressive behavior of gastric cancers,and identification of potential target genes for therapeutic interventions,is a key imperative.  相似文献   
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High fatty acid reduces insulin secretion in pancreatic β-cells and miR-139-5p is increased in dia-betic pancreatic tissues and induces islet β-cell apoptosis.H...  相似文献   
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北京市退耕还林生态效益评估   总被引:6,自引:2,他引:4  
鲁绍伟  李少宁  刘逸菲  徐晓天  赵娜 《生态学报》2021,41(15):6170-6181
基于北京市退耕还林工程区典型样地调查和北京市林业果树科学研究院多年以来对退耕还林生态系统服务功能的监测数据,依据中华人民共和国国家标准《森林生态系统服务功能评估规范》(GB/T 38582-2020)和中华人民共和国林业行业标准《退耕还林工程生态效益监测与评估规范》(LY/T 2573-2016),分别从涵养水源、固碳释氧、保育土壤、林木积累营养物质、净化大气环境和保护生物多样性六项功能指标,对退耕还林生态效益物质量与价值量进行定量评估。结果表明,截至2018年,北京市退耕还林生态系统服务功能总价值量为18.92亿元/a,其中以涵养水源(41.15%)、固碳释氧(26.73%)和净化大气环境(17.27%)分项指标的贡献作用较大。比较北京市退耕还林工程行政区间生态效益价值量大小,发现退耕面积和北京城市总体规划中各行政区功能定位为主要影响因素,其中以密云区价值量最大为4.48亿元/a,占北京市退耕还林生态系统服务功能总价值量的25.56%。退耕工程区内板栗(29.51%)、仁用杏(13.54%)、核桃(12.57%)所贡献的生态系统服务功能价值量位列前三。不同林分类型单位面积价值量排序为生态林 > 生态经济兼用林 > 鲜果林。因此,建议遵循生态优先、适地适树、分类施策的原则,制定退耕还林成果保护政策,并根据各行政区生态价值评估结果确定生态补偿额度和补偿年限,为退耕还林分类补偿政策制定、低质低效林分改造和退耕还林生态系统监测网络体系奠定理论与实践基础。  相似文献   
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以侧柏(Platycladus orientalis)和垂柳(Salix babylonica)为研究对象,采用动态顶空套袋采集法和自动热脱附-气相色谱/质谱联用技术来分析这些植物释放的挥发性有机物(VOCs)的组成和释放模式。选择不同的时间和天气条件下的样本进行采集,并记录相关信息。通过对原始数据的分析,确定有益挥发性有机物(BVOCs)的成分和相对百分含量。研究结果显示,侧柏和垂柳在不同季节释放的BVOCs成分主要包括醇类、醛类、烯烃类等其他类化合物,这些有益BVOCs在植物的生理和生态功能中扮演着重要的角色,对于深入了解植物与环境之间的相互作用具有重要意义。侧柏和垂柳释放BVOCs成分在不同季节会有所变化。其次,研究分析了侧柏和垂柳在不同季节中有益BVOCs成分的含量和变动趋势。侧柏在不同季节的释放模式呈现出明显的差异。春季的释放模式呈现出“单峰单谷”曲线,夏季的释放模式呈现出“单峰”曲线,而秋季的释放模式呈现出“双峰单谷”曲线。这表明侧柏在不同季节中的挥发物释放存在明显的季节性变化。相比之下,垂柳的释放模式在不同季节中相对稳定,呈现出一致的“单峰型”曲线。这说明垂柳的挥发物释放...  相似文献   
67.
As a key regulator for hormone activity, human aldo‐keto reductase family 1 member C3 (AKR1C3) plays crucial roles in the occurrence of various hormone‐dependent or independent malignancies. It is a promising target for treating castration‐resistant prostate cancer (CRPC). However, the development of AKR1C3 specific inhibitors remains challenging due to the high sequence similarity to its isoform AKR1C2. Here, we performed a combined in silico study to illuminate the inhibitory preference of 3‐(3,4‐dihydroisoquinolin‐2(1H)‐ylsulfonyl)benzoic acids for AKR1C3 over AKR1C2, of which compound 38 can achieve up to 5000‐fold anti‐AKR1C3 selectivity. Our umbrella sampling (US) simulations together with end‐point binding free energy calculation MM/GBSA uncover that the high inhibition selectivity originates from the different binding modes, namely “Inward” and “Outward,” of this compound series in AKR1C3 and AKR1C2, respectively. In AKR1C3/38, the tetrahydroquinoline moiety of 38 is accommodated inside the SP1 pocket and interacts favorably with surrounding residues, while, in AKR1C2/38, the SP1 pocket is too small to hold the bulky tetrahydroquinoline group that instead moves out of the pocket with 38 transitioning from an “Inward” to an “Outward” state. Further 3D‐QSAR and energy decomposition analyses suggest that SP1 in AKR1C3 prefers to bind with a rigid bicyclic moiety and the modification of the R3 group has important implication for the compound''s activity. This work is the first attempt to elucidate the selectivity mechanism of inhibitors toward AKR1C3 at the atomic level, which is anticipated to propel the development of next‐generation AKR1C3 inhibitors with enhanced efficacy and reduced “off‐target” effect for CRPC therapy.  相似文献   
68.
A novel short-chain scorpion toxin BmP08 was purified from the venom of the Chinese scorpion Buthus martensi Karsch by a combination of gel-filtration, ion exchange, and reversed-phase chromatography. The primary sequence of BmP08 was determined using the tandem MS/MS technique and Edman degradation, as well as results of NMR sequential assignments. It is composed of 31 amino acid residues including six cysteine residues and shares less than 25% sequence identity with the known alpha-KTx toxins. BmP08 shows no inhibitory activity on all tested voltage-dependent and Ca(2+)-activated potassium channels. The 3D-structure of BmP08 has been determined by 2D-NMR spectroscopy and molecular modeling techniques. This toxin adopts a common alpha/beta-motif, but shows a distinctive local conformation and features a 3(10)-helix and a shorter beta-sheet. The unique structure is closely related to the distinct primary sequence of the toxin, especially to the novel arrangement of S-S linkages in the molecule, in which two disulfide bridges (C(i)-C(j) and C(i+3)-C(j+3)) link covalently the 3(10)-helix with one strand of the beta-sheet structure. The electrostatic potential surface analysis of the toxin reveals salt bridges and hydrogen bonds between the basic residues and negatively charged residues nearby in BmP08, which may be unfavorable for its binding with the known voltage-dependent and Ca(2+)-activated potassium channels. Thus, finding the target for this toxin should be an interesting task in the future.  相似文献   
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