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Structural Basis of the Diversity of Adrenergic Receptors

CELL REPORTS 2019年第10期29卷 2929-+页

作者： Qu, Lu Zhou, Qingtong Xu, Yueming Guo, Yu Chen, Xiaoyu Yao, Deqiang Han, Gye Won Liu, Zhi-Jie Stevens, Raymond C. Zhong, Guisheng Wu, Dong zhao, suwen ShanghaiTech Univ iHuman Inst Shanghai 201210 Peoples R China Chinese Acad Sci Inst Biophys Natl Lab Biomacromol Beijing 100101 Peoples R China Univ Chinese Acad Sci Beijing 100049 Peoples R China ShanghaiTech Univ Sch Life Sci & Technol Shanghai 201210 Peoples R China Univ Southern Calif Dept Biol Sci Bridge Inst Los Angeles CA 90089 USA Univ Southern Calif Dept Chem Bridge Inst Los Angeles CA 90089 USA

Adrenergic receptors are highly homologous while at the same time display a wide diversity of ligand and G-protein binding, and understanding this diversity is key for designing selective or biased drugs for them. Here, we determine two crystal structures of the alpha(2A) adrenergic receptor (alpha(2A)AR) in complex with a partial agonist and an antagonist. Key non-conserved residues from the ligand-binding pocket (Phe(7.39) and Tyr(6.55)) to G-protein coupling region (Ile(34.51) and Lys(34.56)) are discovered to play a key role in the interplay between partial agonism and biased signaling of alpha(2A)AR, which provides insights into the diversity of ligand binding and G-protein coupling preference of adrenergic receptors and lays the foundation for the discovery of next-generation drugs targeting these receptors.

关键词： GPCR α2A adrenergic receptor partial agonism biased signaling

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CA3 Pyramidal Neuron Activation Promotes Cognitive Resilience to Inflammation-Induced Cognitive Inflexibility

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CNS NEUROSCIENCE & THERAPEUTICS 2025年第2期31卷 e70271页

作者： Zuo, Wenqiang Fang, suwen Xu, Tiantian Li, Yumeng zhao, Jianshuai Xie, Xiaoyan Wang, Taozhi Hou, Wugang Wang, Minghui Fourth Mil Med Univ Xijing Hosp Dept Anesthesiol & Perioperat Med Xian Peoples R China

Aims Cognitive dysfunction represents a prominent symptom in numerous prevalent mental illnesses, with systemic inflammation induced by cytokines recognized as a critical factor contributing to cognitive impairments. However, a significant proportion of individuals exposed to systemic inflammation do not develop cognitive dysfunction;instead, they exhibit adaptive responses to this adverse condition. This study aims to investigate the neural activity patterns within the hippocampus and the potential mechanisms that mediate cognitive resilience, particularly in the context of inflammation. Methods We investigated the effects of systemic IL-1 beta (Interleukin-1 beta) on learning, spatial memory, and cognitive flexibility using the Barnes maze test (BMT). We further analyzed specific activity changes in the hippocampus of mice exhibiting cognitive resilience versus susceptibility through immunofluorescence, fiber photometry, and behavioral assessments. Additionally, we employed chemogenetic modulation to explore the role of dCA3 pyramidal neurons in cognitive inflexibility induced by systemic inflammation. Results Systemic inflammation induces cognitive inflexibility while leaving learning and memory intact. Notably, dCA3 activity was elevated in cognitively resilient mice compared to their susceptible counterparts. Fiber photometry data revealed higher activity in the dorsal CA3 (dCA3) when the mice approached the previous target quadrant during the reversal stage of BMT. Importantly, the activation of CaMKII+ pyramidal neurons in the dCA3 mitigated cognitive inflexibility induced by systemic IL-1 beta administration. Conclusions Activation of hippocampal dCA3 neurons, rather than dentate gyrus (DG) neurons, enhances cognitive resilience by improving cognitive flexibility during BMT-related paradigm shifting under sustained inflammation.

关键词： cognitive flexibility cognitive resilience cornu ammonis area 3 IL-1 beta systemic inflammation

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Intrinsically Disordered Proteins Link Alternative Splicing and Post-Translational Modifications to Complex Cell Signaling and Reulation

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BIOPHYSICAL JOURNAL 2018年第3期114卷 79A-79A页

作者： Zhou, Jinhong zhao, suwen Dunker, A. K. Shanghai Tech IHuman Inst Shanghai Peoples R China Indiana Univ Biochem & Mol Biol Indianapolis IN 46204 USA

408-Pos

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Genome-wide CRISPR screen identifies FAM49B as a key regulator of actin dynamics and T cell activation

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2018年第17期115卷 E4051-E4060页

作者： Shang, Wanjing Jiang, Yong Boettcher, Michael Ding, Kang Mollenauer, Marianne Liu, Zhongyi Wen, Xiaofeng Liu, Chang Hao, Piliang zhao, suwen McManus, Michael T. Wei, Lai Weiss, Arthur Wang, Haopeng ShanghaiTech Univ Sch Life Sci & Technol Shanghai 201210 Peoples R China Chinese Acad Sci Shanghai Inst Biol Sci Inst Biochem & Cell Biol Shanghai 200031 Peoples R China Univ Chinese Acad Sci Beijing 100049 Peoples R China Univ Calif San Francisco Dept Microbiol & Immunol WM Keck Ctr Noncoding RNAs Ctr Diabet San Francisco CA 94143 USA ShanghaiTech Univ iHuman Inst Shanghai 201210 Peoples R China Univ Calif San Francisco Dept Med Rosalind Russell & Ephraim P Engleman Rheumatol R Div Rheumatol San Francisco CA 94143 USA Univ Calif San Francisco Howard Hughes Med Inst San Francisco CA 94143 USA Sun Yat Sen Univ Zhongshan Ophthalm Ctr State Key Lab Ophthalmol Guangzhou 510060 Guangdong Peoples R China

Despite decades of research, mechanisms controlling T cell activation remain only partially understood, which hampers T cell-based immune cancer therapies. Here, we performed a genome-wide CRISPR screen to search for genes that regulate T cell activation. Our screen confirmed many of the known regulators in proximal T cell receptor signaling and, importantly, also uncovered a previously uncharacterized regulator, FAM49B (family with sequence similarity 49 member B). FAM49B deficiency led to hyperactivation of Jurkat T cells following T cell receptor stimulation, as indicated by enhancement of CD69 induction, PAK phosphorylation, and actin assembly. FAM49B directly interacted with the active form of the small GTPase Rac, and genetic disruption of the FAM49BRac interaction compromised FAM49B function. Thus, FAM49B inhibits T cell activation by repressing Rac activity and modulating cytoskeleton reorganization.

关键词： genome-wide CRISPR screen TCR signaling FAM49B Rac1 actin cytoskeleton

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Transition-Linker Containing Detergents for Membrane Protein Studies

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CHEMISTRY-A EUROPEAN JOURNAL 2022年第69期28卷 e202202242-e202202242页

作者： Luo, Weiling Yang, Meifang zhao, Yitian Wang, Huixia Yang, Xiaodi Zhang, Wei zhao, Fei zhao, suwen Tao, Houchao Shanghai Univ Tradit Chinese Med Shanghai Frontiers Sci Ctr TCM Chem Biol Innovat Res Inst Tradit Chinese Med Shanghai 201203 Peoples R China ShanghaiTech Univ iHuman Inst Shanghai 201210 Peoples R China ShanghaiTech Univ Sch Life Sci & Technol Shanghai 201210 Peoples R China Hebei Normal Univ Coll Chem & Mat Sci Shijiazhuang 050024 Hebei Peoples R China

It is a pressing need, but still challenging to explore the structure and function of membrane proteins (MPs). One of the main obstacles is the limited availability of matched detergents for the handling of specific MPs. We describe herein the design of new detergents by incorporation of a transition linker between the hydrophilic head and the hydrophobic tail. This design allows a gradual change of hydrophobicity between the outside and inside of micelles, in contrast to the abrupt switch in conventional detergents. Notably, many of these detergents assembled into micelles in while retaining low critical micelle concentrations. Meanwhile, thermal stabilizing evaluation identified superior detergents for representative MPs, including G protein-coupled receptors and a transporter protein. Among them, further improved the NMR study of MPs. We anticipate these that results will encourage future detergent expansion through new remodeling on the traditional detergent scaffold.

关键词： detergents membrane proteins micelles NMR spectroscopy transition linkers

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Glutaryl-CoA dehydrogenase suppresses tumor progression and shapes an anti-tumor microenvironment in hepatocellular carcinoma

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JOURNAL OF HEPATOLOGY 2024年第5期81卷 847-861页

作者： Lao, Yuanxiang Cui, Xiaohan Xu, Zhu Yan, Hongyao Zhang, Zechuan Zhang, Zhenwei Geng, Longpo Li, Binghua Lu, Yijun Guan, Qifei Pu, Xiaohong zhao, suwen Zhu, Jiapeng Qin, Xihu Sun, Beicheng Anhui Med Univ Affiliated Hosp 1 Affiliated Drum Tower Hosp Dept Hepatobiliary Surg Hefei Peoples R China Nanjing Univ Med Sch Affiliated Drum Tower Hosp Dept Hepatobiliary Surg Nanjing Peoples R China Innovat Inst Tumor Immun & Med ITIM Hefei Anhui Peoples R China Anhui Prov Key Lab Tumor Immune Microenvironm & Im Hefei Anhui Peoples R China Shandong Univ Qilu Hosp Cheeloo Coll Med Dept Gastrointestinal Surg Jinan Shandong Peoples R China Sichuan Univ West China Hosp Dept Rheumatol & Immunol Chengdu Sichuan Peoples R China Nanjing Univ Affiliated Drum Tower Hosp Med Sch Dept Pathol Nanjing Jiangsu Peoples R China Shanghai Tech Univ iHuman Inst Shanghai Peoples R China Nanjing Univ Chinese Med Sch Med & Holist Integrat Med Nanjing Jiangsu Peoples R China Nanjing Med Univ Affiliated Changzhou Peoples Hosp 2 Dept Hepatobiliary Pancreat Surg Changzhou Jiangsu Peoples R China Anhui Med Univ Affiliated Hosp 1 218 Jixi Rd Hefei 230022 Peoples R China

Background & aims: Crotonylation, a crotonyl-CoA-based non-enzymatic protein translational modification, affects diverse biological processes, such as spermatogenesis, tissue injury, inflammation, and neuropsychiatric diseases. Crotonylation is decreased in hepatocellular carcinomas (HCCs), but the mechanism remains unknown. In this study, we aim to describe the role of glutaryl-CoA dehydrogenase (GCDH) in tumor suppression. Methods: Three cohorts containing 40, 248 and 17 pairs of samples were used to evaluate the link between GCDH expression levels and clinical characteristics of HCC, as well as responses to anti-programmed cell death protein 1 (PD-1) treatment. Subcutaneous xenograft, orthotopic xenograft, Trp53(Delta hep/Delta hep);MYC- and Ctnnb(oe);METoe-driven mouse models were adopted to validate the effects of GCDH on HCC suppression. Results: GCDH depletion promoted HCC growth and metastasis, whereas its overexpression reversed these processes. As GCDH converts glutaryl-CoA to crotonyl-CoA to increase crotonylation levels, we performed lysine crotonylome analysis and identified the pentose phosphate pathway (PPP) and glycolysis-related proteins PGD, TKT, and ALDOC as GCDH-induced crotonylation targets. Crotonyl-bound targets showed allosteric effects that controlled their enzymatic activities, leading to decreases in ribose 5-phosphate and lactate production, further limiting the Warburg effect. PPP blockade also stimulated peroxidation, synergizing with senescent modulators to induce senescence in GCDH(high) cells. These cells induced the infiltration of immune cells by the SASP (senescence-associated secretory cell phenotype) to shape an anti-tumor immune microenvironment. Meanwhile, the GCDH(low) population was sensitized to anti-PD-1 therapy. Conclusion: GCDH inhibits HCC progression via crotonylation-induced suppression of the PPP and glycolysis, resulting in HCC cell senescence. The senescent cell further shapes an anti-tumor microenvironment via the

关键词： Glutaryl-CoA dehydrogenase Hepatocellular carcinoma Lysine crotonylation Pentose phosphate pathway

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ULK2 deficiency stratifies autophagy-driven molecular subtypes and exacerbates trophoblasts apoptosis in preeclampsia

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PLACENTA 2025年 167卷 42-54页

作者： Gan, Jianfeng Zhou, Wenhan zhao, Huanqiang Shao, Jiejie Cui, Yutong Wu, suwen Xu, Huangfang Wang, Yinan Zhou, Qiongjie Li, Xiaotian Fudan Univ Obstet & Gynecol Hosp Fangxie Rd 419 Shanghai Peoples R China Shanghai Key Lab Female Reprod Endocrine Related D Shanghai Peoples R China Southern Med Univ Affiliated Shenzhen Matern & Child Healthcare Hosp Shenzhen Peoples R China Tongji Univ Shanghai Funiirst Matern & Infant Hosp Sch Med Shanghai Peoples R China Huazhong Univ Sci & Technol Union Hosp Tongji Med Coll Wuhan Peoples R China Zhejiang Univ Affiliated Hosp 2 Sch Med Dept Gynecol Hangzhou Peoples R China

Introduction: Preeclampsia (PE), a placenta-originated hypertensive disorder of pregnancy, lacks targeted therapies despite its significant contribution to maternal and fetal morbidity. Emerging evidence implicates autophagy dysregulation in PE pathogenesis, though its molecular heterogeneity remains unexplored. This study aims to investigate autophagy-related molecular subtypes in PE and identify ULK2 key regulators linking autophagic imbalance to placental dysfunction. Methods: Placental transcriptomic datasets were analyzed to identify autophagy-related differentially expressed genes (ARGs). Unsupervised consensus clustering stratified 80 PE patients into molecular subtypes. Proteinprotein interaction (PPI) networks, machine learning algorithms, and functional enrichment analyses were employed to delineate hub genes and pathways. ULK2's role was validated via qRT-PCR, shRNA knockdown in HTR8/SVneo trophoblasts, and immunofluorescence. A murine PE model was established using the ULK1/2 inhibitor MRT68921 to assess systolic blood pressure, fetal growth, and placental autophagy-apoptosis dynamics. Results: Unsupervised clustering of 45 ARGs classified PE patients into ULK2low and ULK2high subtypes. The ULK2low subtype exhibited severe clinical features: elevated preterm delivery, systolic hypertension, HELLP syndrome incidence and increased proteinuria. ULK2-kncokdown trophoblasts showed impaired autophagy and upregulated apoptosis. Six hub genes correlated with disease severity and inversely with ULK2 expression. In mice, ULK2 inhibition induced PE-like phenotypes: sustained hypertension, fetal growth restriction and severe proteinuria. Discussion: ULK2 deficiency disrupts trophoblast homeostasis, driving placental dysfunction and severe clinical outcomes. The ULK2low subtype highlights autophagy heterogeneity in PE. While pharmacological ULK2 inhibition recapitulates PE in mice, limitations include sample size and MRT68921's dual ULK1/2 activity. Our findings prop

关键词： Preeclampsia Autophagy Subtype Bioinformatics Apoptosis

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GPCRana: A web server for quantitative analysis of GPCR structures

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STRUCTURE 2023年第9期31卷 1132-1142.e2页

作者： Guo, Yu Zhou, Qingtong Wei, Bin Wang, Ming-Wei zhao, suwen ShanghaiTech Univ iHuman Inst Shanghai 201210 Peoples R China ShanghaiTech Univ Sch Life Sci & Technol Shanghai 201210 Peoples R China Univ Chinese Acad Sci Beijing 100049 Peoples R China Chinese Acad Sci Shanghai Inst Nutr & Hlth Shanghai 200031 Peoples R China Fudan Univ Sch Basic Med Sci Dept Pharmacol Shanghai 200032 Peoples R China Res Ctr Deepsea Bioresources Sanya 572025 Hainan Peoples R China Univ Tokyo Sch Sci Dept Chem Tokyo 1130033 Japan

G protein-coupled receptors (GPCRs) attract tremendous attention from both industrial and academic researchers with currently over 900 released structures. Structural analysis is widely used to understand receptor functionality and pharmacology, but more user-friendly tools are needed. Residue-residue contact score (RRCS) is an atomic distance-based method that allows a quantitative description of GPCR structures. Here, we present GPCRana, a web server that provides a user-friendly interface to analyze GPCR structures. After uploading selected structures, GPCRana immediately generates a comprehensive report covering four aspects: (i) RRCS for all residue pairs incorporated with real-time 3D visualization;(ii) ligand-receptor interactions;(iii) activation pathway analysis;and (iv) RRCS_TMs that indicates the global movements of trans membrane helices. Moreover, conformational changes between two structures can be analyzed. Applying GPCRana on AlphaFold2-predicted models reveals differentiated inter-helical packing forms in a receptor dependent manner. Our web server offers a fast and precise way to study GPCR structures and is freely available at http://***/#/.

关键词： GPCR residue-residue contact score web server structure analysis GPCR activation protein-ligand interactions

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Integrated multi-omics characterization of neuroblastoma with bone or bone marrow metastasis

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Genes & Diseases 2025年第3期12卷 382-396页

作者： Kai Huang Linyu Yang Yue Ma Lijian Cao suwen Li Zhenzhen zhao Jianwu Zhou Shan Wang Department of Pediatric Surgical Oncology The Children’s Hospital of Chongqing Medical UniversityNational Clinical Research Center for Child Health and DisordersMinistry of Education Key Laboratory of Child Development and DisordersChongqing Key Laboratory of Pediatric Metabolism and Inflammatory DiseasesChongqing 400014China

The pathogenesis of neuroblastoma with bone or bone marrow metastasis (NB-BBM)and its complex immune microenvironment remain poorly elucidated, hampering the advancement of effective risk prediction for BBM and limiting therapeutic strategies. Feature recognition of 142 paraffin-embedded hematoxylin-eosin-stained tumor section images was conductedusing a Swin-Transformer for pathological histology to predict NB-BBM occurrence. Single-celltranscriptomics identified a tumor cell subpopulation (NB3) and two tumor-associated macrophage (TAM) subpopulations (SPP1^(+) TAMs and IGHM^(+) TAMs) closely associated with BBM andhighlighted transketolase (TKT) as a key molecular marker for metastatic progression in *** extensive multi-omics investigation into NB-BBM enhances our understanding of single-celltranscriptional dynamics in NB beyond existing research, outlining the evolution from in situcarcinoma through tumorigenesis to bone marrow metastases. Furthermore, exploration ofthe immune microenvironment identified specific subpopulations of TAMs crucial in promotingNB-BBM, presenting new avenues for immunotherapy. These insights enhance our understanding of the metastatic process from NB to BBM and facilitate the development of more effectivediagnostic and therapeutic strategies for this aggressive pediatric cancer.

关键词： Bone marrow metastasis Bone metastasis Immunotherapy Multi-omics Neuroblastoma Transketolase(TKT)

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A computational evaluation of targeted oxidation strategy (TOS) for potential inhibition of SARS-CoV-2 by disulfiram and analogues

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BIOPHYSICAL CHEMISTRY 2021年 276卷 106610-106610页

作者： Xu, Luyan Tong, Jiahui Wu, Yiran zhao, suwen Li, Bo-Lin ShanghaiTech Univ Sch Phys Sci & Technol Shanghai 201210 Peoples R China ShanghaiTech Univ iHuman Inst Shanghai 201210 Peoples R China ShanghaiTech Univ Sch Life Sci & Technol Shanghai 201210 Peoples R China Chinese Acad Sci Shanghai Adv Res Inst Shanghai 201210 Peoples R China Chinese Acad Sci Shanghai Inst Organ Chem Shanghai 200032 Peoples R China Chinese Acad Sci Shanghai Inst Biol Sci CAS MPG Partner Inst Computat Biol Key Lab Computat Biol Shanghai 200031 Peoples R China Univ Chinese Acad Sci Beijing 100049 Peoples R China

In the new millennium, the outbreak of new coronavirus has happened three times: SARS-CoV, MERS-CoV, and SARS-CoV-2. Unfortunately, we still have no pharmaceutical weapons against the diseases caused by these viruses. The pandemic of SARS-CoV-2 reminds us the urgency to search new drugs with totally different mechanism that may target the weaknesses specific to coronaviruses. Herein, we disclose a computational evaluation of targeted oxidation strategy (TOS) for potential inhibition of SARS-CoV-2 by disulfiram, a 70-year-old antialcoholism drug, and predict a multiple-target mechanism. A preliminary list of promising TOS drug candidates targeting the two thiol proteases of SARS-CoV-2 are proposed upon virtual screening of 32,143 disulfides.

关键词： Coronavirus SARS-CoV-2 COVID-19 Target oxidation strategy Disulfide Thiol protease

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