Proteins: Structure最新文献

英文中文

Mutation in MCL1 predicted loop to helix structural transition stabilizes MCL1-Bax binding interaction favoring cancer cell survival. MCL1突变预测环向螺旋结构转变，稳定MCL1- bax结合相互作用，有利于癌细胞存活。

Proteins: Structure

Pub Date : 2022-09-01 Epub Date: 2022-04-23 DOI: 10.1002/prot.26347

Eby-Nesar Stella-Glory Deepak Shyl, Beutline Malgija, Appadurai Muthamil Iniyan, Samuel Gnana Prakash Vincent

Myeloid cell leukemia-1 (MCL1), an anti-apoptotic BCL-2 family protein plays a major role in the control of apoptosis as the regulator of mitochondrial permeability which is deregulated in various solid and hematological malignancies. Interaction of the executioner proteins Bak/Bax with anti-apoptotic MCL1 and its cellular composition determines the apoptotic or survival pathway. Mutations act at various levels in the apoptotic process and can contribute to disease. Single nucleotide polymorphism (SNP) in MCL1 gene was focused as they result in changes in the amino acid sequence and have been associated with tumorigenesis. This study highlighted the deleterious MCL1-Bax stabilizing effect of the mutation V220F on MCL1 structure through computational protein-protein interaction predictions and molecular dynamics simulations. The single point mutation at V220F was selected as it is residing at the hydrophobic core region of BH3 conserved domain, the site of Bax binding. The molecular dynamics simulation studies showed increase in stability of the mutated MCL1 before and after Bax binding comparable with the native MCL1. The clusters from free energy landscape found out structural variation in folding pattern with additional helix near the BH3 domain in the mutated structure. This loop to helix structural change in the mutated complex favored stable interaction of the complex and also induced Bax conformational change. Moreover, molecular mechanics-based binding free energy calculations confirmed increased affinity of Bax toward mutated MCL1. Residue-wise interaction network analysis showed the individual residues in Bax binding responsible for the change in stability and interaction due to the protein mutation. In conclusion, the overall findings from the study reveal that the presence of V220F mutation on MCL1 is responsible for the structural confirmational change leading to disruption of its biological functions which might be responsible for tumorigenesis. The mutation could possibly be used as future diagnostic markers in treating cancers.

髓样细胞白血病-1 （MCL1）是一种抗凋亡的BCL-2家族蛋白，作为线粒体通透性的调节因子，在多种实体和血液恶性肿瘤中发挥重要作用。刽子手蛋白Bak/Bax与抗凋亡的MCL1及其细胞组成的相互作用决定了凋亡或存活途径。突变在细胞凋亡过程中起着不同程度的作用，并可能导致疾病。MCL1基因的单核苷酸多态性（SNP）引起了氨基酸序列的改变，并与肿瘤的发生有关。本研究通过计算蛋白-蛋白相互作用预测和分子动力学模拟，强调了突变V220F对MCL1结构的有害稳定MCL1- bax作用。选择V220F的单点突变，是因为它位于BH3保守结构域的疏水核心区，即Bax结合位点。分子动力学模拟研究表明，与原生MCL1相比，突变MCL1在与Bax结合前后的稳定性有所提高。从自由能景观中发现，在突变结构中，BH3结构域附近有额外的螺旋，折叠模式发生了变化。这种环向螺旋结构的变化有利于复合物的稳定相互作用，也引起了Bax构象的变化。此外，基于分子力学的结合自由能计算证实了Bax对突变MCL1的亲和力增加。基于残基的相互作用网络分析表明，由于蛋白质突变，Bax结合中的单个残基负责稳定性和相互作用的变化。综上所述，本研究的总体结果表明，MCL1上V220F突变的存在导致了结构确认性改变，导致其生物学功能的破坏，这可能是肿瘤发生的原因。这种突变可能被用作未来治疗癌症的诊断标记。

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引用次数: 0

Issue Information ‐ Forthcoming 发行信息‐即将发布

Proteins: Structure

Pub Date : 2022-08-05 DOI: 10.1002/prot.26123

Arnab Mukherjee

引用次数: 0

Issue Information ‐ Table of Content 发行信息‐内容表

Proteins: Structure

Pub Date : 2022-08-05 DOI: 10.1002/prot.26122

引用次数: 0

Issue Information ‐ Forthcoming 发行信息‐即将发布

Proteins: Structure

Pub Date : 2022-07-08 DOI: 10.1002/prot.26119

Wenxue Zhou, Zhongjie Han, Zhixiang Wu, Weikang Gong, Shuang Yang, Lei Chen, Chunhua Li, Luke R. Vass, Katie M. Branscum, R. Bourret, Clay A. Foster, A. Mobeen, B. L. Puniya, Srinivasan Ramachandran, Krisztina Varga, Harish Vashisth, Ashutosh Prakash Dubey, Vijay Shankar Singh, Rajeev Mishra, Anil Kumar Tripathi, Arshad Hosseini, Nikolay V. Dokholyan, Jiaan Yang, Wen Xiang Cheng, Xiao Fei Zhao, Gang Wu, Shi Tong Sheng, Qiyue Hu

引用次数: 0

Issue Information ‐ Table of Content 发行信息‐内容表

Proteins: Structure

Pub Date : 2022-07-08 DOI: 10.1002/prot.26118

引用次数: 0

Issue Information ‐ Table of Content 发行信息‐内容表

Proteins: Structure

Pub Date : 2022-06-06 DOI: 10.1002/prot.26114

引用次数: 0

Specific recognition between YTHDF3 and m6A‐modified RNA: An all‐atom molecular dynamics simulation study YTHDF3和m6A修饰RNA的特异性识别:全原子分子动力学模拟研究

Proteins: Structure

Pub Date : 2022-05-31 DOI: 10.1002/prot.26389

Wenxue Zhou, Zhongjie Han, Zhixiang Wu, Weikang Gong, Shuang Yang, Lei Chen, Chunhua Li

The YTH domain of YTHDF3 belongs to a class of protein “readers” recognizing the N6‐methyladenosine (m6A) modification in mRNA. Although static crystal structure reveals m6A recognition by a conserved aromatic cage, the dynamic process in recognition and importance of aromatic cage residues are not completely clear. Here, molecular dynamics (MD) simulations are performed to explore the issues and negative selectivity of YTHDF3 toward unmethylated substrate. Our results reveal that there exist conformation selectivity and induced‐fit in YTHDF3 binding with m6A‐modified RNA, where recognition loop and loop6 play important roles in the specific recognition. m6A modification enhances the stability of YTHDF3 in complex with RNA. The methyl group of m6A, like a warhead, enters into the aromatic cage of YTHDF3, where Trp492 anchors the methyl group and constraints m6A, making m6A further stabilized by π–π stacking interactions from Trp438 and Trp497. In addition, the methylation enhances the hydrophobicity of adenosine, facilitating water molecules excluded out of the aromatic cage, which is another reason for the specific recognition and stronger intermolecular interaction. Finally, the comparative analyses of hydrogen bonds and binding free energy between the methylated and unmethylated complexes reveal the physical basis for the preferred recognition of m6A‐modified RNA by YTHDF3. This study sheds light on the mechanism by which YTHDF3 specifically recognizes m6A‐modified RNA and can provide important information for structure‐based drug design.

YTHDF3的YTH结构域属于一类识别mRNA中N6‐甲基腺苷(m6A)修饰的蛋白质“读者”。虽然静态晶体结构揭示了保守芳香笼对m6A的识别，但芳香笼残基识别的动态过程和重要性尚不完全清楚。本文通过分子动力学(MD)模拟来探讨YTHDF3对未甲基化底物的负选择性。结果表明，YTHDF3与m6A修饰的RNA结合存在构象选择性和诱导拟合，其中识别环和loop6在特异性识别中起重要作用。m6A修饰增强了YTHDF3与RNA复合物的稳定性。m6A的甲基像弹头一样进入YTHDF3的芳香笼中，Trp492锚定甲基并约束m6A，通过Trp438和Trp497的π -π堆叠相互作用使m6A进一步稳定。此外，甲基化增强了腺苷的疏水性，有利于将水分子排除在芳香笼外，这也是腺苷具有特异性识别和更强分子间相互作用的另一个原因。最后，通过对比分析甲基化和未甲基化复合物之间的氢键和结合自由能，揭示了YTHDF3优先识别m6A修饰RNA的物理基础。该研究揭示了YTHDF3特异性识别m6A修饰RNA的机制，并可为基于结构的药物设计提供重要信息。

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引用次数: 3

A computational approach to investigate constitutive activation of NF‐κB 研究NF - κB组成激活的计算方法

Proteins: Structure

Pub Date : 2022-05-27 DOI: 10.1002/prot.26388

A. Mobeen, B. L. Puniya, S. Ramachandran

Nuclear factor kappa B (NF‐κB) signaling is the master regulator of inflammatory pathways; therefore, its regulation has been the subject of investigation since last two decades. Multiple models have been published that describes the dynamics of NF‐κB activity by stimulated activation and feedback loops. However, there is also paramount evidence of the critical role of posttranslational modifications (PTMs) in the regulation of NF‐κB pathway. With the premise that PTMs present alternate routes for activation or repression of the NF‐κB pathway, we have developed a model including all PTMs known so far describing the system behavior. We present a pathway network model consisting of 171 proteins forming 315 molecular species and consisting of 482 reactions that describe the NF‐κB activity regulation in totality. The overexpression or knockdown of interacting molecular partners that regulate NF‐κB transcriptional activity by PTMs is used to infer the dynamics of NF‐κB activity and offers qualitative agreement between model predictions and the experimental results heuristically. Finally, we have demonstrated an instance of NF‐κB constitutive activation through positive upregulation of cytokines (the stimuli) and IKK complex (NF‐κB activator), the characteristic features in several cancer types and metabolic disorders, and its reversal by employing combinatorial activation of PPARG, PIAS3, and P50‐homodimer. For the first time, we have presented a NF‐κB model that includes transcriptional regulation by PTMs and presented a theoretical strategy for the reversal of NF‐κB constitutive activation. The presented model would be important in understanding the NF‐κB system, and the described method can be used for other pathways as well.

核因子κB (NF‐κB)信号是炎症通路的主要调节因子;因此，近二十年来，其监管一直是人们研究的主题。已有多个模型通过刺激激活和反馈回路描述了NF‐κB活性的动力学。然而，也有重要的证据表明，翻译后修饰(PTMs)在NF - κB通路的调节中起着关键作用。在假设PTMs存在激活或抑制NF - κB通路的替代途径的前提下，我们开发了一个模型，包括迄今为止已知的描述系统行为的所有PTMs。我们提出了一个通路网络模型，该模型由171个蛋白质组成，形成315个分子种，由482个反应组成，总体上描述了NF‐κB活性调节。通过ptm调节NF - κB转录活性的相互作用分子伴侣的过表达或敲低被用来推断NF - κB活性的动态，并在模型预测和实验结果之间提供了启发式的定性一致。最后，我们通过细胞因子(刺激因子)和IKK复合物(NF - κB激活因子)的正向上调证明了NF - κB构成性激活的实例，这是几种癌症类型和代谢紊乱的特征，并通过组合激活PPARG、PIAS3和P50 -同型二聚体来逆转。我们首次提出了一个包括ptm转录调控的NF - κB模型，并提出了一个逆转NF - κB构成激活的理论策略。所提出的模型对于理解NF - κB系统很重要，所描述的方法也可以用于其他途径。

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引用次数: 0

Pep–Whisperer: Inhibitory peptide design 胡椒耳语者:抑制肽设计

Proteins: Structure

Pub Date : 2022-05-22 DOI: 10.1002/prot.26384

N. Hurwitz, D. Zaidman, H. Wolfson

Designing peptides for protein–protein interaction inhibition is of significant interest in computer‐aided drug design. Such inhibitory peptides could mimic and compete with the binding of the partner protein to the inhibition target. Experimental peptide design is a laborious, time consuming, and expensive multi‐step process. Therefore, in silico peptide design can be beneficial for achieving this task. We present a novel algorithm, Pep–Whisperer, which aims to design inhibitory peptides for protein–protein interaction. The desirable peptides would have a relatively high predicted binding affinity to the target protein in a given protein–protein complex. The algorithm outputs linear peptides which are based on an initial template. The template could either be a peptide which is retrieved from the interaction site, or a patch of nonconsecutive amino acids from the protein–protein interface which is completed to a linear peptide by short polyalanine linkers. In addition, the algorithm takes into consideration the conservation of the amino acids in the ligand‐protein binding site by using evolutionary information for choosing the preferred amino acids in each position of the designed peptide. Our algorithm was able to design peptides with high predicted binding affinity to the target protein. The method is fully automated and available as a web server at http://bioinfo3d.cs.tau.ac.il/PepWhisperer/.

设计蛋白质相互作用抑制肽是计算机辅助药物设计的重要内容。这种抑制肽可以模仿和竞争伴侣蛋白与抑制靶点的结合。实验肽设计是一个费力、耗时和昂贵的多步骤过程。因此，在硅肽设计可以有利于实现这一任务。我们提出了一种新的算法，Pep-Whisperer，旨在设计蛋白质-蛋白质相互作用的抑制肽。在给定的蛋白-蛋白复合物中，期望的肽对目标蛋白具有相对高的预测结合亲和力。该算法输出基于初始模板的线性肽。模板可以是从相互作用位点提取的肽，也可以是由短聚丙氨酸连接物完成的蛋白质-蛋白质界面上的不连续氨基酸片段。此外，该算法还考虑了配体-蛋白结合位点氨基酸的保守性，利用进化信息选择设计肽的每个位置的首选氨基酸。我们的算法能够设计出与目标蛋白具有高预测结合亲和力的肽。该方法是完全自动化的，可作为web服务器访问http://bioinfo3d.cs.tau.ac.il/PepWhisperer/。

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引用次数: 3

Deciphering the role of the two conserved motifs of the ECF41 family σ factor in the autoregulation of its own promoter in Azospirillum brasilense Sp245 解读巴西氮螺旋菌Sp245中ECF41家族σ因子的两个保守基序在其自身启动子自动调控中的作用

Proteins: Structure

Pub Date : 2022-05-17 DOI: 10.1002/prot.26387

Ekta Pathak, A. Dubey, V. Singh, Rajeev Mishra, A. Tripathi

In Azospirillum brasilense, an extra‐cytoplasmic function σ factor (RpoE10) shows the characteristic 119 amino acid long C‐terminal extension found in ECF41‐type σ factors, which possesses three conserved motifs (WLPEP, DGGGR, and NPDKV), one in the linker region between the σ2 and σ4, and the other two in the SnoaL_2 domain of the C‐terminal extension. Here, we have described the role of the two conserved motifs in the SnoaL_2 domain of RpoE10 in the inhibition and activation of its activity, respectively. Truncation of the distal part of the C‐terminal sequence of the RpoE10 (including NPDKV but excluding the DGGGR motif) results in its promoter's activation suggesting autoregulation. Further truncation of the C‐terminal sequence up to its proximal part, including NPDKV and DGGGR motif, abolished promoter activation. Replacement of NPDKV motif with NAAAV in RpoE10 increased its ability to activate its promoter, whereas replacement of DGGGR motif led to reduced promoter activation. We have explored the dynamic modulation of σ2 ‐σ4 domains and the relevant molecular interactions mediated by the two conserved motifs of the SnoaL2 domain using molecular dynamics simulation. The analysis enabled us to explain that the NPDKV motif located distally in the C‐terminus negatively impacts transcriptional activation. In contrast, the DGGGR motif found proximally of the C‐terminal extension is required to activate RpoE10.

在巴西偶氮螺旋菌中，胞质外功能σ因子(RpoE10)具有ECF41型σ因子特有的119个氨基酸长的C末端延伸，具有3个保守基序(WLPEP、DGGGR和NPDKV)，一个位于σ2和σ4之间的连接区，另外两个位于C末端延伸的SnoaL_2结构域。在这里，我们分别描述了RpoE10的SnoaL_2结构域的两个保守基序在抑制和激活其活性中的作用。RpoE10 C末端序列的末端部分(包括NPDKV但不包括DGGGR基序)的截断导致其启动子的激活，提示自动调节。进一步截断C端序列直至其近端部分，包括NPDKV和DGGGR基序，取消启动子激活。用NAAAV替换RpoE10中的NPDKV基序增加了其激活启动子的能力，而替换DGGGR基序导致启动子激活降低。本文采用分子动力学模拟的方法，探讨了SnoaL2结构域的两个保守基序对σ2‐σ4结构域的动态调制和相关的分子相互作用。该分析使我们能够解释位于C端远端的NPDKV基序对转录激活产生负面影响。相比之下，在C末端延伸的近端发现的DGGGR基序是激活RpoE10所必需的。

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