排序方式: 共有82条查询结果,搜索用时 15 毫秒
61.
Xue-Ni Hou Dr. Naotaka Sekiyama Yasuko Ohtani Dr. Feng Yang Dr. Yohei Miyanoiri Dr. Ken-ichi Akagi Prof. Dr. Xun-Cheng Su Prof. Dr. Hidehito Tochio 《Chemphyschem》2021,22(14):1505-1517
Linear polyubiquitin chains regulate diverse signaling proteins, in which the chains adopt various conformations to recognize different target proteins. Thus, the structural plasticity of the chains plays an important role in controlling the binding events. Herein, paramagnetic NMR spectroscopy is employed to explore the conformational space sampled by linear diubiquitin, a minimal unit of linear polyubiquitin, in its free state. Rigorous analysis of the data suggests that, regarding the relative positions of the ubiquitin units, particular regions of conformational space are preferentially sampled by the molecule. By combining these results with further data collected for charge-reversal derivatives of linear diubiquitin, structural insights into the factors underlying the binding events of linear diubiquitin are obtained. 相似文献
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We capture and compare the polarization response of a solvated globular protein ubiquitin to static electric (E-fields) using atomistic molecular dynamics simulations. We collectively follow E-field induced changes, electrical and structural, occurring across multiple trajectories using the magnitude of the protein dipole vector ( P p ). E-fields antiparallel to P p induce faster structural changes and more facile protein unfolding relative to parallel fields of the same strength. While weak E-fields (0.1–0.5 V/nm) do not unfold ubiquitin and produce a reversible polarization, strong E-fields (1–2 V/nm) unfold the protein through a pathway wherein the helix:β-strand interactions rupture before those for the β1-β5 clamp. Independent of E-field direction, high E-field induced structural changes are also reversible if the field is switched off before P p exceeds 2 times its equilibrium value. We critically examine the dependence of water properties, protein rotational diffusion and E-field induced protein unfolding pathways on the thermostat/barostat parameters used in our simulations. 相似文献
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Dr. Robbert Q. Kim Dr. Mohit Misra Dr. Alexis Gonzalez Ines Tomašković Dr. Donghyuk Shin Prof. Dr. Hermann Schindelin Dr. Dmitri V. Filippov Prof. Dr. Huib Ovaa Prof. Dr. Ivan Đikić Dr. Gerbrand J. van der Heden van Noort 《Chemistry (Weinheim an der Bergstrasse, Germany)》2021,27(7):2506-2512
Legionnaires’ disease is caused by infection with the intracellularly replicating Gram-negative bacterium Legionella pneumophila. This pathogen uses an unconventional way of ubiquitinating host proteins by generating a phosphoribosyl linkage between substrate proteins and ubiquitin by making use of an ADPribosylated ubiquitin (UbADPr) intermediate. The family of SidE effector enzymes that catalyze this reaction is counteracted by Legionella hydrolases, which are called Dups. This unusual ubiquitination process is important for Legionella proliferation and understanding these processes on a molecular level might prove invaluable in finding new treatments. Herein, a modular approach is used for the synthesis of triazole-linked UbADPr, and analogues thereof, and their affinity towards the hydrolase DupA is determined and hydrolysis rates are compared to natively linked UbADPr. The inhibitory effects of modified Ub on the canonical eukaryotic E1-enzyme Uba1 are investigated and rationalized in the context of a high-resolution crystal structure reported herein. Finally, it is shown that synthetic UbADPr analogues can be used to effectively pull-down overexpressed DupA from cell lysate. 相似文献
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Guo-Chao Chu Xiao Hua Chong Zuo Chen-Chen Chen Dr. Xian-Bin Meng Dr. Zhongping Zhang Dr. Yao Fu Dr. Jing Shi Dr. Yi-Ming Li 《Chemistry (Weinheim an der Bergstrasse, Germany)》2019,25(72):16668-16675
The development of powerful and general methods to acquire ubiquitin (Ub) chains has prompted the deciphering of Ub-mediated processes. Herein, the cysteine-aminoethylation assisted chemical ubiquitination (CAACU) strategy is extended and improved to enable the efficient semi-synthesis of atypical Ub chain analogues and Ub-based probes. Combining the Cys aminoethylation and the auxiliary-mediated protein ligation, several linkage- and length-defined atypical Ub chains including di-Ubs, K27C-linked tri-Ub, K11/K48C-branched tri-Ub, and even the SUMOlated Ub are successfully prepared from recombinantly expressed starting materials at about a 9–20 mg L−1 expression level. In addition, the utility of this strategy is demonstrated with the synthesis of a novel non-hydrolyzable di-Ub PA probe, which may provide a new useful tool for the mechanistic studies of deubiquitinase (DUB) recognition. 相似文献
65.
《Mendeleev Communications》2022,32(6):747-749
The glutarimide moiety, common in many immuno-modulatory drugs, was decorated with lactam and diamide side chains via two variants of the Ugi reaction, namely, with isocyanide, aldehyde and acid or with isocyanide and oxo acid. The resulting diastereomerically pure compounds were evaluated for their affinity towards the E3 ubiquitin ligase substrate receptor Cereblon. 相似文献
66.
Chemical Synthesis of Phosphorylated Ubiquitin and Diubiquitin Exposes Positional Sensitivities of E1‐E2 Enzymes and Deubiquitinases
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Dr. Somasekhar Bondalapati Wissam Mansour Dr. Mark A. Nakasone Dr. Suman Kumar Maity Prof. Michael H. Glickman Prof. Ashraf Brik 《Chemistry (Weinheim an der Bergstrasse, Germany)》2015,21(20):7360-7364
Modification of ubiquitin by phosphorylation extends the signaling possibilities of this dynamic signal, as it could affect the activity of ligases and the processing of ubiquitin chains by deubiquitinases. The first chemical synthesis of phosphorylated ubiquitin and of Lys63‐linked diubiquitin at the proximal, distal or both ubiquitins is reported. This enabled the examination of how such a modification alters E1‐E2 activities of the ubiquitination machinery. It is found that E1 charging was not affected, while the assembly of phosphorylated ubiquitin chains was differentially inhibited with E2 enzymes tested. Moreover, this study shows that phosphorylation interferes with the recognition of linkage specific antibodies and the activities of several deubiquitinases. Notably, phosphorylation in the proximal or distal ubiquitin unit has differential effects on specific deubiquitinases. These results support a unique role of phosphorylation in the dynamics of the ubiquitin signal. 相似文献
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Qingyun Zheng Tian Wang Guo‐Chao Chu Chong Zuo Rui Zhao Xin Sui Linzhi Ye Yuanyuan Yu Jingnan Chen Xiangwei Wu Wenhao Zhang Haiteng Deng Jing Shi Man Pan Yi‐Ming Li Lei Liu 《Angewandte Chemie (International ed. in English)》2020,59(32):13496-13501
Triazole‐based deubiquitylase (DUB)‐resistant ubiquitin (Ub) probes have recently emerged as effective tools for the discovery of Ub chain‐specific interactors in proteomic studies, but their structural diversity is limited. A new family of DUB‐resistant Ub probes is reported based on isopeptide‐N‐ethylated dimeric or polymeric Ub chains, which can be efficiently prepared by a one‐pot, ubiquitin‐activating enzyme (E1)‐catalyzed condensation reaction of recombinant Ub precursors to give various homotypic and even branched Ub probes at multi‐milligram scale. Proteomic studies using label‐free quantitative (LFQ) MS indicated that the isopeptide‐N‐ethylated Ub probes may complement the triazole‐based probes in the study of Ub interactome. Our study highlights the utility of modern protein synthetic chemistry to develop structurally and new families of tool molecules needed for proteomic studies. 相似文献
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泛素是一种真核细胞信号分子,主要参与蛋白质降解和DNA修复等生命活动.泛素Ser65位被磷酸化之后,在溶液中呈现两个稳定的溶液构象,这两种构象的比例能够被pH调控,本研究利用NMR进一步发现它还受到温度影响.基于该发现,对磷酸化泛素进行了19F化学标记,利用19F NMR方法表征了不同温度下磷酸化泛素两种构象的比例,发现两者比例变化与温度之间的关系可以通过线性方程来描述,利用该方程可以通过构象比例计算样品内部温度,因此可以作为一种基于NMR检测的温度传感器.本文所开发的基于19F化学标记磷酸化泛素的温度传感器不仅能够作为体外样品温度检测的有力工具,还有望用于检测细胞内部的温度.从而有助于揭示生物学特性和功能. 相似文献