Review
Physiology
Megan T. Lewno, Taixing Cui, Xuejun Wang
Summary: Cardiomyocyte death in the form of apoptosis and necrosis is a major cellular mechanism underlying cardiac pathogenesis, with recent research revealing that not all necrosis is accidental and there are multiple forms of regulated necrosis. Perturbation of Cullin deneddylation in cardiomyocytes impairs both the ubiquitin-proteasome system and the autophagic-lysosomal pathway.
FRONTIERS IN PHYSIOLOGY
(2021)
Review
Oncology
Wenqi Du, Ruicheng Zhang, Bilal Muhammad, Dongsheng Pei
Summary: The COP9 signalosome (CSN) is a protein complex composed of 8 subunits that play crucial roles in cell proliferation, tumorigenesis, and DNA damage repair. CSN acts as a regulator at the intersection between neddylation and ubiquitination in cancer progression. Individual CSN subunits have potential as therapeutic targets for cancer therapy through regulation of transcription factors and the cell cycle.
CANCER BIOLOGY & MEDICINE
(2022)
Article
Biochemistry & Molecular Biology
Yeong-Mu Kim, Hye-Ji Kim, Dong-Kyu Kim, Dong-Hyun Jung, Hyo Je Cho, Sangjune Kim, Jihoon Nah, Sang-Min Jang
Summary: Cullin-RING E3 ubiquitin ligases spatially and temporally regulate the degradation of cellular proteins, and the speed of this regulation depends on the binding strength between each CUL and CSN5. The NAE inhibitor can rapidly inhibit NEDD8ylation in most CULs, while the deneddylation of CUL2 is slower.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Dana Harshuk-Shabso, Noam Castel, Ran Israeli, Sheri Harari, Elah Pick
Summary: The study revealed that the yeast CSN possesses a highly conserved cullin deneddylase core complex, and can be utilized for researching CSN deneddylation and testing the efficacy of inhibitors.
Article
Multidisciplinary Sciences
Yaru Zhang, Marco Jost, Ryan A. Pak, Daniel Lu, Jing Li, Brett Lomenick, Spiros D. Garbis, Chi-Ming Li, Jonathan S. Weissman, James Russell Lipford, Raymond J. Deshaies
Summary: Cop9 signalosome (CSN) regulates the function of cullin-RING E3 ubiquitin ligases (CRLs) by deconjugating the ubiquitin-like protein NEDD8 from the cullin subunit. In this study, quantitative mass spectrometry and genome-wide CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa) screens were used to identify factors that modulate cell viability upon inhibition of CSN. The study found that CRL components and regulators strongly modulate the antiproliferative effects of CSN inhibition, and identified two pathways involved in genome integrity that contribute to the toxicity of CSN inhibition.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Review
Immunology
Xiaoying Zhang, Yu'e Liu, Tong Zhang, Yuying Tan, Xiangpeng Dai, Yong-Guang Yang, Xiaoling Zhang
Summary: Cullin-RING ligases (CRLs) are crucial regulators of the stability and activity of proteins related to the development of autoimmune diseases (AIDs), which involve complex signaling pathways. Understanding the underlying regulatory mechanisms of AIDs is important for developing effective therapeutic strategies. CRLs play critical roles in regulating AIDs through key inflammation-associated pathways and targeting them may lead to novel therapeutic approaches.
FRONTIERS IN IMMUNOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Stephanie Diaz, Kankan Wang, Benita Sjogren, Xing Liu
Summary: Maintenance of protein homeostasis is crucial for eukaryotic biology, and the ubiquitin-proteasome system (UPS) plays an important role in the pathogenesis of cardiovascular diseases. Recent research has found that cullin-RING ubiquitin ligases (CRLs), an essential component of UPS, have significant physiological and pathological functions in the cardiovascular system.
Review
Pharmacology & Pharmacy
Yifan Chen, Xuejing Shao, Ji Cao, Hong Zhu, Bo Yang, Qiaojun He, Meidan Ying
Summary: The crosstalk between phosphorylation and ubiquitination plays a crucial role in tumorigenesis, providing new directions and strategies for tumor therapy.
ACTA PHARMACEUTICA SINICA B
(2021)
Review
Pharmacology & Pharmacy
Qianqian Song, Siqi Feng, Wenjun Peng, Anqi Li, Ting Ma, Bin Yu, Hong-Min Liu
Summary: Gastric carcinoma poses a serious threat to human health with high morbidity and mortality rates. The ubiquitination modification, specifically involving CRLs, plays a crucial role in the pathogenesis of gastric carcinoma by regulating various cellular pathways. Targeting a certain CULs member neddylation may be a promising strategy for selectively controlling cellular protein levels in cancer treatment.
PHARMACOLOGICAL RESEARCH
(2021)
Review
Biochemistry & Molecular Biology
Qiyin Zhou, Yawen Zheng, Yi Sun
Summary: This review highlights the importance of mitochondria as the powerhouse of a cell, regulated by multiple signaling pathways. Post-translational modification like neddylation plays a crucial role in cellular metabolism and is involved in regulating the morphology, trafficking, and function of mitochondria. Understanding the mechanisms of how neddylation modulates mitochondria will advance our knowledge in mitochondrial regulation.
CELL AND BIOSCIENCE
(2021)
Article
Biochemistry & Molecular Biology
Vu Thuy Khanh Le-Trilling, Sofia Banchenko, Darius Paydar, Pia Madeleine Leipe, Lukas Binting, Simon Lauer, Andrea Graziadei, Robin Klingen, Christine Gotthold, Joerg Buerger, Thilo Bracht, Barbara Sitek, Robert Jan Lebbink, Anna Malyshkina, Thorsten Mielke, Juri Rappsilber, Christian M. T. Spahn, Sebastian Voigt, Mirko Trilling, David Schwefel
Summary: This study revealed that rat cytomegalovirus infection induces the loss of transcription factor STAT2, which is crucial for antiviral interferon signaling. It was found that viral protein E27 exploits the host-cell CRL4 complexes to degrade STAT2 through poly-ubiquitylation. Furthermore, structural analyses showed that E27 recruits STAT2 through a bipartite binding interface, partially overlapping with the IRF9 binding site.
Article
Immunology
Huiqing Xiu, Yanmei Peng, Xiaofang Huang, Jiali Gong, Jie Yang, Jiachang Cai, Kai Zhang, Wei Cui, Yingying Shen, Jianli Wang, Shufang Zhang, Zhijian Cai, Gensheng Zhang
Summary: Neddylation activation in macrophages plays a critical protective role against MRSA infection by increasing ROS production. Inhibiting neddylation may lead to liver and kidney injury and increased mortality in MRSA infection, suggesting a new non-antibiotic treatment strategy.
JOURNAL OF IMMUNOLOGY
(2021)
Article
Plant Sciences
Changhyun Choi, Jong Hee Im, Jinjeong Lee, Soon Il Kwon, Woe-Yeon Kim, Sang Ryeol Park, Duk-Ju Hwang
Summary: This study shows that OsDWD1 in rice suppresses immune responses by degrading OsNPR1. OsDWD1 acts as a negative regulator of the immune response, and OsNPR1 is its substrate. The CUL4-based E3 ligase system also influences OsNPR1 protein levels in Arabidopsis.
Article
Multidisciplinary Sciences
Haibin Zhou, Jianfeng Lu, Krishnapriya Chinnaswamy, Jeanne A. Stuckey, Liu Liu, Donna McEachern, Chao-Yie Yang, Denzil Bernard, Hong Shen, Liangyou Rui, Yi Sun, Shaomeng Wang
Summary: The study identifies two potent and selective covalent DCN1 inhibitors that selectively inhibit cullin-3 neddylation in cells, leading to increased NRF2 protein levels and protection of mice from liver damage.
NATURE COMMUNICATIONS
(2021)
Article
Pharmacology & Pharmacy
Jayaprakasam Bolleddula, Hao Chen, Lawrence Cohen, Xiaofei Zhou, Sandeepraj Pusalkar, Allison Berger, Farhad Sedarati, Karthik Venkatakrishnan, Swapan K. Chowdhury
Summary: This study characterizes the metabolism and clearance mechanisms of pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, after intravenous administration to cancer patients. Major circulating metabolites of pevonedistat have higher exposure in nonclinical toxicological species than in humans, with minimal contribution to pharmacological activity.
DRUG METABOLISM AND DISPOSITION
(2022)
Review
Chemistry, Medicinal
Qing Wang, Yu Zhou, Jianhui Huang, Niu Huang
Summary: Significant progress has been made in the research of the 5-HT2BR receptor since its characterization in 1992. The receptor is implicated in regulating various biological functions and diseases across different areas, with crystal complex structures providing insights for drug development.
Review
Chemistry, Medicinal
Mengdi Shang, Kuan Lu, Wenli Guan, Shujie Cao, Mengtian Ren, Chuanzheng Zhou
Summary: The cGAS-STING pathway is a vital part of the innate immune system, with 2',3'-cGAMP serving as a key second messenger. Research on 2',3'-cGAMP analogues for immunotherapeutic potential has been increasingly popular over the past decade.
Article
Multidisciplinary Sciences
Jie Chen, Nan Liu, Yinpin Huang, Yuanxun Wang, Yuxing Sun, Qingcui Wu, Dianrong Li, Shuanhu Gao, Hong-Wei Wang, Niu Huang, Xiangbing Qi, Xiaodong Wang
Summary: Molecular glues like anagrelide, nauclefine, and DNMDP induce apoptosis by forming complexes with PDE3A and SLFN12, as demonstrated in the high-resolution cryo-EM structures presented in this study. The designed analogs of anagrelide showed enhanced interactions with SLFN12, leading to superior efficacy in inducing apoptosis in cultured cells and tumor xenografts.
NATURE COMMUNICATIONS
(2021)
Review
Chemistry, Multidisciplinary
Mengtian Ren, Marc M. Greenberg, Chuanzheng Zhou
Summary: This article summarizes the mechanistic studies of DNA damage and repair in reconstituted nucleosome core particles (NCPs) in the past decade. The research reveals that histones actively participate in DNA damage and repair processes in diverse ways, impacting chromatin structure and function, and making significant contributions to epigenetics. These findings enrich our understanding of the roles of histone proteins in DNA damage and repair, and have important biological implications.
ACCOUNTS OF CHEMICAL RESEARCH
(2022)
Article
Multidisciplinary Sciences
Jian-Hua Wang, Yu-Liang Tang, Zhou Gong, Rohit Jain, Fan Xiao, Yu Zhou, Dan Tan, Qiang Li, Niu Huang, Shu-Qun Liu, Keqiong Ye, Chun Tang, Meng-Qiu Dong, Xiaoguang Lei
Summary: This study develops a new cross-linker called DOPA2 for rapid chemical cross-linking mass spectrometry analysis, which captures the conformations of protein unfolding intermediates. Compared with traditional cross-linkers, DOPA2 shows unique advantages in terms of speed, structural agreement, and adaptability. Additionally, this method allows for time-course analysis of protein conformational changes during denaturant-induced unfolding.
NATURE COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Linjie Li, Hanyi Liao, Yumin Meng, Weiwei Li, Pengcheng Han, Kefang Liu, Qing Wang, Dedong Li, Yanfang Zhang, Liang Wang, Zheng Fan, Yuqin Zhang, Qiyue Wang, Xin Zhao, Yeping Sun, Niu Huang, Jianxun Qi, George Fu Gao
Summary: The study reveals the differences in binding affinities between the four early sub-variants of the Omicron variant and human ACE2 receptor, providing insights into the structural basis for these differences.
Article
Multidisciplinary Sciences
Xiao Teng, Sijia Chen, Qing Wang, Zhao Chen, Xiaoying Wang, Niu Huang, Sanduo Zheng
Summary: G protein-coupled receptors (GPCRs) are the largest family of membrane receptors and the most important drug targets. This study reports the structures of the D1 dopamine receptor and mini-G(s) complex, providing insights into the molecular mechanisms of G protein activation.
Article
Biochemistry & Molecular Biology
Fengwei Zhang, Sarah O. K. Mak, Yuchu Liu, Ya Ke, Feng Rao, Wing Ho Yung, Li Zhang, Billy Kwok Chong Chow
Summary: This study reveals the neural mechanism of secretin in managing thirst in the central nervous system. The results demonstrate that the local ablation of SCT receptor (SCTR) in the subfornical organ (SFO) reduces water intake in dehydrated mice, while salt intake remains unaffected. Furthermore, it is found that SCT elicits inward currents in the neuronal nitric oxide synthase (SFOnNOS) neurons via SCTR in the presence of glutamate receptor antagonists.
Article
Chemistry, Medicinal
Hui Zhu, Jincai Yang, Niu Huang
Summary: This study investigates the scoring functions used in structure-based virtual screening, finding that machine-learning scoring functions (MLSFs) have unsatisfactory generalization capacity. By combining target-specific patterns with features shared among similar compounds, better performance can be achieved. Therefore, it is recommended to assess the generalization ability of MLSFs using the Pfam-cluster approach and to be cautious with the features learned by MLSFs.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Article
Chemistry, Multidisciplinary
Min Xu, Cheng Shen, Jincai Yang, Qing Wang, Niu Huang
Summary: In recent years, large-scale structure-based virtual screening has gained increasing interest for identifying novel compounds corresponding to potential drug targets. Understanding the strengths and weaknesses of docking algorithms is critical for improving their success rate in practical applications. In this study, the docking successes and failures of two representative docking programs, UCSF DOCK 3.7 and AutoDock Vina, were systematically investigated. The results showed that DOCK 3.7 performed better in early enrichment and exhibited superior computational efficiency, while Vina scoring function exhibited a bias towards compounds with higher molecular weights.
Review
Biochemistry & Molecular Biology
Hui Zhu, Yulin Zhang, Wei Li, Niu Huang
Summary: Structure-based virtual screening, also known as molecular docking, has gained increasing application in the early stage of drug discovery for discovering small-molecule ligands based on protein structures. This review comprehensively surveys the prospective applications of molecular docking with solid experimental validations. The analysis includes the novelty of targets and docking hits, practical protocols of docking screening, and the subsequent experimental validations. The majority of virtual screenings were performed on widely studied targets, with only a small portion focused on less-explored new targets. GLIDE is the most popular docking software, while the DOCK 3 series excels in large-scale virtual screening. The identified hits are promising in structural novelty, with a quarter of them exhibiting better potency than 1 μM. However, most studies only conducted in vitro bioassays for validation, potentially limiting the further characterization and development of the active compounds.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Multidisciplinary Sciences
Junliang Wang, Wei Chen, Wenjun Yue, Wenhong Hou, Feng Rao, Hanbing Zhong, Yuanming Qi, Ni Hong, Ting Ni, Wenfei Jin
Summary: This study developed a single-cell polyadenylation sequencing method to investigate the landscape of alternative polyadenylation (APA) at the single-cell level. The results showed that genes with multiple polyA sites in bulk data tend to use only one site in each single cell. Cell cycle genes were found to have high variation in polyA site usages. Furthermore, polyA site usage switch played an important role in cell cycle regulation.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Multidisciplinary Sciences
Yifei Zhou, Hongjun Li, Yi Huang, Jiahui Li, Guiyu Deng, Gong Chen, Zhen Xi, Chuanzheng Zhou
Summary: During solid-phase peptide synthesis (SPPS), the main side reactions of protected amino acids are hard to remove. The authors here report a thiol-labile amino protecting group, DNPBS, which greatly suppresses these side reactions observed in conventional SPPS. Although DNPBS SPPS is less efficient than Fmoc SPPS, they can be combined to synthesize peptides that are otherwise difficult to obtain.
NATURE COMMUNICATIONS
(2023)
Review
Biochemistry & Molecular Biology
Lu ZHOU, Feng RAO
Summary: COP1 is a RING E3 ligase that was first discovered in plants and plays a crucial role in establishing photomorphogenesis. It has been found that COP1 is involved in a complex regulatory network that mediates light/darkness or temperature response, connecting light sensor modules to core transcription factors and affecting cellular metabolism and growth. Although the functions and signaling pathways of COP1 in mammals are largely unknown, it still plays a critical role in regulating metabolism and cell growth during tumorigenesis. The importance of COP1 in cellular processes makes it of great significance in biology.
PROGRESS IN BIOCHEMISTRY AND BIOPHYSICS
(2023)
Review
Biochemistry & Molecular Biology
Guangchen Li, Yifu Cheng, Chi Han, Chun Song, Niu Huang, Yunfei Du
Summary: Drugs containing pyrazole nucleus have shown a broad spectrum of biological activities, including anti-inflammatory, antipsychotic, and analgesic effects. Research suggests that drugs with pyrazole nucleus may exhibit better pharmacokinetics and pharmacological effects compared to drugs containing similar heterocyclic rings.
RSC MEDICINAL CHEMISTRY
(2022)