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Correction: Dynamic properties of dipeptidyl peptidase III from Bacteroides thetaiotaomicron and the structural basis for its substrate specificity – a computational study 修正:来自拟杆菌的二肽基肽酶III的动态特性及其底物特异性的结构基础-一项计算研究
IF 3.743 Q2 Biochemistry, Genetics and Molecular Biology Pub Date : 2017-11-13 DOI: 10.1039/C7MB90042B
M. Tomin and S. Tomić

Correction for ‘Dynamic properties of dipeptidyl peptidase III from Bacteroides thetaiotaomicron and the structural basis for its substrate specificity – a computational study’ by M. Tomin et al., Mol. BioSyst., 2017, 13, 2407–2417.

修正了M. Tomin等人的“来自拟杆菌的二肽基肽酶III的动态特性及其底物特异性的结构基础——一项计算研究”,Mol. BioSyst。浙江农业学报,2017,13,2407-2417。
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引用次数: 0
Pharmacology of predatory and defensive venom peptides in cone snails 锥体蜗牛掠夺性和防御性毒液肽的药理学研究
IF 3.743 Q2 Biochemistry, Genetics and Molecular Biology Pub Date : 2017-11-01 DOI: 10.1039/C7MB00511C
Jutty Rajan Prashanth, Sebastien Dutertre and Richard James Lewis

Cone snails are predatory gastropods whose neurotoxic venom peptides (conotoxins) have been extensively studied for pharmacological probes, venom evolution mechanisms and potential therapeutics. Conotoxins have a wide range of structural and functional classes that continue to undergo accelerated evolution that underlies the rapid expansion of the genus over their short evolutionary history. A number of pharmacological classes, driven by separately evolved defensive and predatory venoms, have been hypothesised to facilitate shifts in prey that exemplify the adaptability of cone snails. Here we provide an overview of these pharmacological families and discuss their ecological roles and evolutionary impact.

圆锥蜗牛是一种掠食性腹足类动物,其神经毒性毒液肽(conotoxins)已被广泛研究用于药理学探针,毒液进化机制和潜在的治疗方法。Conotoxins有广泛的结构和功能类别,继续经历加速进化,这是在其短暂的进化历史中迅速扩张的基础。许多药理分类,分别由进化的防御性和掠食性毒液驱动,已经被假设为促进猎物的转变,这是锥体蜗牛适应性的例证。在这里,我们提供这些药理家族的概述,并讨论他们的生态作用和进化影响。
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引用次数: 27
Staphylococcus aureus extracellular vesicles (EVs): surface-binding antagonists of biofilm formation† 金黄色葡萄球菌细胞外囊泡:生物膜形成的表面结合拮抗剂†
IF 3.743 Q2 Biochemistry, Genetics and Molecular Biology Pub Date : 2017-10-30 DOI: 10.1039/C7MB00365J
Hansol Im, Sujin Lee, Steven A. Soper and Robert J. Mitchell

The prevalence of Staphylococcus aureus worldwide as a nosocomial infectious agent is recognized but the reason behind the spread of this bacterium has remained elusive. Here, we hypothesized that the communication of S. aureus might benefit from it blocking other bacteria from establishing themselves on the surface. This was found to be the case for several pathogens as the S. aureus supernatant curtailed their ability to form biofilms. Subsequent analyses using Acinetobacter baumannii as a model found this effect is primarily mediated by S. aureus’ extracellular vesicles (EVs), which bound to the polystyrene surface. We found the EV-treated surfaces were significantly more hydrophilic after EV treatment, a condition that made it difficult for A. baumannii to initially adhere to the polystyrene surface and reduced its resulting biofilm by up to 93%. Subsequent tests found this also extended to several other bacterial pathogens, with a 40–70% decrease in their biofilm mass. The S. aureus EVs and their activity still remained after the surface was washed with 10% bleach, while the use of ethylenediaminetetraacetic acid (EDTA) removed both the EVs from the surface and their activity.

金黄色葡萄球菌作为一种医院感染因子在世界范围内的流行是公认的,但这种细菌传播背后的原因仍然难以捉摸。在这里,我们假设金黄色葡萄球菌的交流可能受益于它阻止其他细菌在表面建立自己。这被发现是一些病原体的情况,因为金黄色葡萄球菌上清削弱了它们形成生物膜的能力。随后以鲍曼不动杆菌为模型的分析发现,这种作用主要是由金黄色葡萄球菌的细胞外囊泡(ev)介导的,这些囊泡与聚苯乙烯表面结合。我们发现,经过EV处理的表面明显更亲水,这种情况使得鲍曼不动杆菌难以最初粘附在聚苯乙烯表面,并使其产生的生物膜减少了93%。随后的测试发现,这种情况也适用于其他几种细菌病原体,它们的生物膜质量减少了40-70%。用10%漂白剂洗涤表面后,金黄色葡萄球菌EVs及其活性仍然存在,而使用乙二胺四乙酸(EDTA)去除表面的EVs及其活性。
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引用次数: 22
Mechanism of the formation of the RecA–ssDNA nucleoprotein filament structure: a coarse-grained approach RecA-ssDNA核蛋白丝结构的形成机制:粗粒度方法
IF 3.743 Q2 Biochemistry, Genetics and Molecular Biology Pub Date : 2017-10-27 DOI: 10.1039/C7MB00486A
Goutam Mukherjee, Arumay Pal and Yaakov Levy

In prokaryotes, the RecA protein catalyzes the repair and strand exchange of double-stranded DNA. RecA binds to single-stranded DNA (ssDNA) and forms a presynaptic complex in which the protein polymerizes around the ssDNA to form a right-handed helical nucleoprotein filament structure. In the present work, the mechanism for the formation of the RecA–ssDNA filament structure is modeled using coarse-grained molecular dynamics simulations. Information from the X-ray structure was used to model the protein itself but not its interactions; the interactions between the protein and the ssDNA were modeled solely by electrostatic, aromatic, and repulsive energies. For the present study, the monomeric, dimeric, and trimeric units of RecA and 4, 8, and 11 NT-long ssDNA, respectively, were studied. Our results indicate that monomeric RecA is not sufficient for nucleoprotein filament formation; rather, dimeric RecA is the elementary binding unit, with higher multimeric units of RecA facilitating filament formation. Our results reveal that loop region flexibility at the primary binding site of RecA is essential for it to bind the incoming ssDNA, that the aromatic residues present in the loop region play an important role in ssDNA binding, and that ATP may play a role in guiding the ssDNA by changing the electrostatic potential of the RecA protein.

在原核生物中,RecA蛋白催化双链DNA的修复和链交换。RecA结合单链DNA (ssDNA)并形成突触前复合物,其中蛋白质在ssDNA周围聚合形成右手螺旋核蛋白丝结构。在目前的工作中,RecA-ssDNA细丝结构的形成机制采用粗粒度分子动力学模拟建模。来自x射线结构的信息被用来模拟蛋白质本身,而不是它的相互作用;蛋白质与ssDNA之间的相互作用仅通过静电能、芳香能和排斥能来模拟。在本研究中,分别研究了RecA的单体、二聚体和三聚体单元以及4、8和11 nt -长ssDNA。我们的研究结果表明,单体RecA不足以形成核蛋白丝;相反,二聚体RecA是基本的结合单元,较高的多聚体RecA单元促进了细丝的形成。我们的研究结果表明,RecA初级结合位点环区柔韧性对其结合进入的ssDNA至关重要,环区存在的芳香残基在ssDNA结合中起重要作用,ATP可能通过改变RecA蛋白的静电电位来引导ssDNA。
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引用次数: 3
Conformational heterogeneity in tails of DNA-binding proteins is augmented by proline containing repeats† 含有脯氨酸的重复序列†增加了dna结合蛋白尾部的构象异质性
IF 3.743 Q2 Biochemistry, Genetics and Molecular Biology Pub Date : 2017-10-26 DOI: 10.1039/C7MB00412E
Harshavardhan Khare, Debayan Dey, Chilakapati Madhu, Dillip Senapati, Srinivasarao Raghothama, Thimmaiah Govindaraju and Suryanarayanarao Ramakumar

A cationic terminal extension or tail is a common feature of many DNA-binding proteins. We show that a particular type of tail rich in proline, alanine and lysine belongs to the class of ‘flexible disorder’ and consists of characteristic pentapeptide repeats. Our designed peptides, (AAKKA)1–4 and (PAKKA)1–4, represent the tails of several bacterial DNA-binding proteins. Enhanced conformational sampling of these representative peptides using accelerated molecular dynamic simulations supported by circular dichroism spectroscopy and nuclear magnetic resonance studies demonstrates the role of frequent and interspersed prolines in augmenting conformational heterogeneity of the peptide backbone. Analysis of circular variance of backbone dihedral angles indicates alternating regions of relative rigidity and flexibility along the peptide sequence due to prolines. Preferred placement of lysines in the regions of higher backbone flexibility might improve DNA-binding by conformational selection. Our results could be relevant for rational de novo design of disordered peptides.

阳离子末端延伸或尾部是许多dna结合蛋白的共同特征。我们表明,富含脯氨酸、丙氨酸和赖氨酸的一种特殊类型的尾部属于“柔性紊乱”类,由特征五肽重复组成。我们设计的肽(AAKKA) 1-4和(PAKKA) 1-4代表了几种细菌dna结合蛋白的尾部。利用圆二色光谱和核磁共振研究支持的加速分子动力学模拟对这些代表性肽进行了增强的构象采样,证明了频繁和分散的脯氨酸在增强肽主链构象异质性中的作用。主二面角的圆形变化分析表明,由于脯氨酸的作用,沿肽序列存在相对刚性和柔性的交替区域。赖氨酸在高骨干柔韧性区域的优先位置可能通过构象选择改善dna结合。我们的结果可能与无序肽的合理从头设计有关。
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引用次数: 3
Development of an AlphaLISA high throughput technique to screen for small molecule inhibitors targeting protein arginine methyltransferases† AlphaLISA高通量筛选蛋白精氨酸甲基转移酶小分子抑制剂技术的发展
IF 3.743 Q2 Biochemistry, Genetics and Molecular Biology Pub Date : 2017-10-25 DOI: 10.1039/C7MB00391A
Lakshmi Prabhu, Lan Chen, Han Wei, Özlem Demir, Ahmad Safa, Lifan Zeng, Rommie E. Amaro, Bert H. O’Neil, Zhon-Yin Zhang and Tao Lu

The protein arginine methyltransferase (PRMT) family of enzymes comprises nine family members in mammals. They catalyze arginine methylation, either monomethylation or symmetric/asymmetric dimethylation of histone and non-histone proteins. PRMT methylation of its substrate proteins modulates cellular processes such as signal transduction, transcription, and mRNA splicing. Recent studies have linked overexpression of PRMT5, a member of the PRMT superfamily, to oncogenesis, making it a potential target for cancer therapy. In this study, we developed a highly sensitive (Z′ score = 0.7) robotic high throughput screening (HTS) platform to discover small molecule inhibitors of PRMT5 by adapting the AlphaLISA? technology. Using biotinylated histone H4 as a substrate, and S-adenosyl-L-methionine as a methyl donor, PRMT5 symmetrically dimethylated H4 at arginine (R) 3. Highly specific acceptor beads for symmetrically dimethylated H4R3 and streptavidin-coated donor beads bound the substrate, emitting a signal that is proportional to the methyltransferase activity. Using this powerful approach, we identified specific PRMT5 inhibitors P1608K04 and P1618J22, and further validated their efficacy and specificity for inhibiting PRMT5. Importantly, these two compounds exhibited much more potent efficacy than the commercial PRMT5 inhibitor EPZ015666 in both pancreatic and colorectal cancer cells. Overall, our work highlights a novel, powerful, and sensitive approach to identify specific PRMT5 inhibitors. The general principle of this HTS screening method can not only be applied to PRMT5 and the PRMT superfamily, but may also be extended to other epigenetic targets. This approach allows us to identify compounds that inhibit the activity of their respective targets, and screening hits like P1608K04 and P1618J22 may serve as the basis for novel drug development to treat cancer and/or other diseases.

在哺乳动物中,蛋白精氨酸甲基转移酶(PRMT)家族由9个家族成员组成。它们催化精氨酸甲基化,组蛋白和非组蛋白的单甲基化或对称/不对称二甲基化。PRMT底物蛋白的甲基化调节细胞过程,如信号转导、转录和mRNA剪接。最近的研究将PRMT5 (PRMT超家族成员)的过表达与肿瘤发生联系起来,使其成为癌症治疗的潜在靶点。在这项研究中,我们开发了一个高灵敏度(Z ' score = 0.7)的机器人高通量筛选(HTS)平台,通过适应AlphaLISA?技术。PRMT5以生物素化组蛋白H4为底物,s -腺苷- l-蛋氨酸为甲基供体,在精氨酸(R) 3处对称二甲基化H4。对称二甲基化H4R3的高特异性受体珠和链霉亲和素包被的供体珠结合底物,发出与甲基转移酶活性成正比的信号。利用这种强大的方法,我们鉴定出特异性的PRMT5抑制剂P1608K04和P1618J22,并进一步验证了它们抑制PRMT5的有效性和特异性。重要的是,这两种化合物在胰腺癌和结直肠癌细胞中都表现出比商业化的PRMT5抑制剂EPZ015666更有效的疗效。总的来说,我们的工作强调了一种新的、强大的、敏感的方法来识别特定的PRMT5抑制剂。这种HTS筛选方法的一般原理不仅可以应用于PRMT5和PRMT超家族,还可以推广到其他表观遗传靶点。这种方法使我们能够识别抑制其各自靶点活性的化合物,并且筛选像P1608K04和P1618J22这样的靶点可能作为治疗癌症和/或其他疾病的新药开发的基础。
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引用次数: 24
Imbalance in amino acid and purine metabolisms at the hypothalamus in inflammation-associated depression by GC-MS† GC-MS研究炎症相关性抑郁症中下丘脑氨基酸和嘌呤代谢失衡
IF 3.743 Q2 Biochemistry, Genetics and Molecular Biology Pub Date : 2017-10-25 DOI: 10.1039/C7MB00494J
Yu Wu, Yonghong Li, Yanjuan Jia, Chaojun Wei, Hui Xu, Rui Guo, Yuanting Li, Jing Jia, Xiaoming Qi and Xiaoling Gao

Hypothalamic dysfunction is a key factor in depression; increasing evidence highlights neuroinflammation abnormalities as well as imbalances in neurotransmitters and the purinergic system in the pathophysiology of depression. However, little is known about the metabolomic changes in the hypothalamus of depressed patients with neuroinflammation. Herein, taking advantage of the well-established lipopolysaccharide (LPS)-induced depression mouse model, we measured metabolic changes in the hypothalamus using gas chromatography-mass spectrometry (GC-MS). Sucrose preference test (SPT), open field test (OFT), forced swimming test (FST), and tail suspension test (TST) were conducted to assess our depressive model. To better understand the metabolic disturbances occurring in the hypothalamus of depressed mice, multivariate statistics were applied to analyse the clinical significance of differentially expressed metabolites in the hypothalamus of mice with LPS-induced depression. Bioinformatic analysis was conducted to detect potential relationships among the changed metabolites. The data confirmed that mice with LPS-induced depression were good mimics of depression patients in some characteristic symptoms such as decreased sucrose intake and increased immobility. In our study, 27 differentially expressed metabolites were identified in the hypothalamus of mice with LPS-induced depression. Herein, seventeen of these metabolites decreased, whereas 10 metabolites increased. These molecular changes were closely related to perturbations in the amino acid and purine metabolisms. Our data indicate that dysfunction of amino acid and purine metabolisms is one of main characteristics of inflammation-mediated depression. These results provide new insights into the mechanisms underlying depression, which may shed some light on the role of the hypothalamus in the pathogenesis of inflammation-mediated depression.

下丘脑功能障碍是抑郁症的关键因素;越来越多的证据强调神经炎症异常以及神经递质和嘌呤能系统在抑郁症病理生理中的不平衡。然而,对伴有神经炎症的抑郁症患者下丘脑代谢组学的变化知之甚少。在此,利用已建立的脂多糖(LPS)诱导的抑郁症小鼠模型,我们使用气相色谱-质谱(GC-MS)测量下丘脑的代谢变化。采用蔗糖偏好试验(SPT)、野外试验(OFT)、强迫游泳试验(FST)和悬尾试验(TST)对抑郁模型进行评估。为了更好地了解抑郁症小鼠下丘脑代谢紊乱的情况,我们采用多元统计学方法分析lps诱导抑郁症小鼠下丘脑代谢物差异表达的临床意义。进行生物信息学分析以检测变化的代谢物之间的潜在关系。数据证实,lps诱导的抑郁症小鼠在一些特征症状上很好地模仿抑郁症患者,如减少蔗糖摄入量和增加不动能力。在我们的研究中,在lps诱导的抑郁症小鼠的下丘脑中发现了27种差异表达的代谢物。其中17种代谢物减少,10种代谢物增加。这些分子变化与氨基酸和嘌呤代谢的扰动密切相关。我们的数据表明,氨基酸和嘌呤代谢功能障碍是炎症介导的抑郁症的主要特征之一。这些结果为抑郁症的潜在机制提供了新的见解,这可能会揭示下丘脑在炎症介导的抑郁症发病机制中的作用。
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引用次数: 15
Host immune evasion strategies of malaria blood stage parasite 疟疾血期寄生虫的宿主免疫逃避策略
IF 3.743 Q2 Biochemistry, Genetics and Molecular Biology Pub Date : 2017-10-23 DOI: 10.1039/C7MB00502D
Xue Yan Yam and Peter R. Preiser

Host immune evasion is a key strategy for the continual survival of many microbial pathogens including Apicomplexan protozoan: Plasmodium spp., the causative agent of Malaria. The malaria parasite has evolved a variety of mechanisms to evade the host immune responses within its two hosts: the female Anopheles mosquito vector and vertebrate host. In this review, we will focus on the molecular mechanisms of the immune evasion strategies used by the Plasmodium parasite at the blood stage which is responsible for the clinical manifestations of human malaria. We also aim to provide some insights on the potential targets for malaria interventions through the recent advancement in understanding the molecular biology of the parasite.

宿主免疫逃避是许多微生物病原体持续生存的关键策略,包括顶复合体原生动物:疟原虫,疟疾的病原体。疟疾寄生虫在其两个宿主(雌性疟蚊媒介和脊椎动物宿主)内进化出多种机制来逃避宿主免疫反应。本文就疟原虫在血液阶段的免疫逃避策略的分子机制作一综述,该策略是导致人类疟疾临床表现的主要原因。我们还旨在通过对寄生虫分子生物学的最新了解,为疟疾干预的潜在目标提供一些见解。
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引用次数: 19
An interaction network approach to study the correlation between endocrine disrupting chemicals and breast cancer† 研究内分泌干扰物与乳腺癌相关性的相互作用网络方法
IF 3.743 Q2 Biochemistry, Genetics and Molecular Biology Pub Date : 2017-10-20 DOI: 10.1039/C7MB00489C
Andrea Polo, Chiara Nittoli, Anna Crispo, Teresa Langastro, Stefania Cocco, Lorella Severino, Michelino De Laurentiis, Gennaro Ciliberto, Maurizio Montella, Alfredo Budillon and Susan Costantini

Endocrine disrupting chemicals (EDCs) are natural or synthetic exogenous substances affecting human health. Although present at low concentrations in the environment, they can cause a broad range of negative effects on the endocrine functions by mimicking the action of steroid hormones due to their structural similarity. Hormonal unbalance can play an important role in carcinogenesis at any stage of disease. In the case of the breast cancer, EDCs directly affect the transformation of normal breast cells into cancer cells by interfering with hormonal regulation and by inducing the alteration of factors that regulate gene expression. The principal aims of this work were to study the interaction networks of proteins modulated in breast cancer by either environmental EDCs or mycotoxins, and to identify the proteins with the strongest coordination role defined as hub nodes. Our studies evidenced the presence of seven and six hub proteins in two EDCs and mycotoxins networks, respectively. Then, by merging the two networks, we identified that three hub nodes (BCL2, ESR2 and CTNNB1) in the environmental EDCs network show direct interactions with three hub nodes (CASP8, RELA and MKI67) in the mycotoxins network. These data highlighted that two networks are linked through proteins involved in the apoptosis regulation and in processes related to cell proliferation and survival, and, thus, in breast cancer progression.

内分泌干扰物是影响人体健康的天然或合成外源性物质。虽然它们在环境中的浓度很低,但由于它们的结构相似性,它们可以模仿类固醇激素的作用,对内分泌功能产生广泛的负面影响。在疾病的任何阶段,激素失衡都可能在癌变中发挥重要作用。在乳腺癌中,EDCs通过干扰激素调节和诱导调节基因表达的因子的改变,直接影响正常乳腺细胞向癌细胞的转化。这项工作的主要目的是研究环境EDCs或真菌毒素在乳腺癌中调节的蛋白质相互作用网络,并确定具有最强协调作用的蛋白质,定义为枢纽节点。我们的研究证明,在两个EDCs和真菌毒素网络中分别存在7个和6个枢纽蛋白。然后,通过合并这两个网络,我们发现环境EDCs网络中的三个枢纽节点(BCL2、ESR2和CTNNB1)与真菌毒素网络中的三个枢纽节点(CASP8、RELA和MKI67)存在直接相互作用。这些数据强调了两个网络通过参与细胞凋亡调节和细胞增殖和存活相关过程的蛋白质联系在一起,因此,在乳腺癌进展中。
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引用次数: 0
Model system based proteomics to understand the host response during bacterial infections 模型系统为基础的蛋白质组学,以了解宿主在细菌感染期间的反应
IF 3.743 Q2 Biochemistry, Genetics and Molecular Biology Pub Date : 2017-10-19 DOI: 10.1039/C7MB00372B
Arumugam Kamaladevi, Shanmugam Marudhupandiyan and Krishnaswamy Balamurugan

Infectious diseases caused by bacterial pathogens pose a major concern to public health and, thus, greater attention must be given to providing insightful knowledge on host–pathogen interactions. There are several theories addressing the dynamics of complex mechanisms of host–pathogen interactions. The availability of an ample number of universally accepted model systems, including vertebrates, invertebrates, and mammalian cells, provides in-depth transcriptomics data to evaluate these complex mechanisms during host–pathogen interactions. Recent model system based proteomic studies have addressed the issues related to human diseases by establishing the protein profile of model animals that closely resemble the environment. As a result, model system based proteomics has been widely accepted as a powerful and effective approach to understand the highly complex host–pathogen interfaces at their protein levels. This review offers a snapshot of the contributions of selective model systems on host–bacterial pathogen interactions through proteomic approaches.

由细菌病原体引起的传染病对公共卫生构成重大关切,因此,必须更加重视提供关于宿主-病原体相互作用的深刻知识。有几个理论解决宿主-病原体相互作用的复杂机制的动力学。大量普遍接受的模型系统(包括脊椎动物、无脊椎动物和哺乳动物细胞)的可用性为评估宿主-病原体相互作用过程中的这些复杂机制提供了深入的转录组学数据。最近基于模型系统的蛋白质组学研究通过建立与环境密切相似的模型动物的蛋白质谱来解决与人类疾病相关的问题。因此,基于模型系统的蛋白质组学已被广泛接受为一种在蛋白质水平上理解高度复杂的宿主-病原体界面的强大而有效的方法。本文综述了通过蛋白质组学方法对宿主-细菌病原体相互作用的选择性模型系统的贡献。
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引用次数: 2
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Molecular BioSystems
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