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Intrinsically Disordered Proteins Link Alternative Splicing and Post-translational Modifications to Complex Cell Signaling and Regulation

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JOURNAL OF MOLECULAR BIOLOGY 2018年第16期430卷 2342-2359页

作者： Zhou, Jianhong zhao, suwen Dunker, A. Keith ShanghaiTech Univ iHuman Inst 393 Huaxia Middle Rd Shanghai 201210 Peoples R China ShanghaiTech Univ Sch Life Sci & Technol 393 Huaxia Middle Rd Shanghai 201210 Peoples R China Indiana Univ Sch Med Dept Biochem & Mol Biol Ctr Computat Biol & Bioinformat 410 W 10th StSuite 5000 Indianapolis IN 46202 USA

Intrinsically disordered proteins and regions (IDPs and IDRs) lack well-defined tertiary structures, yet carry out various important cellular functions, especially those associated with cell signaling and regulation. In eukaryotes, IDPs and IDRs contain the preferred loci for both alternative splicing (AS) and many post-translational modifications (PTMs). Furthermore, AS and/or PTMs at these loci generally alter the signaling outcomes associated with these IDPs or IDRs, where the functional cooperation of these three features is named the IDP-AS-PTM toolkit. However, the prevalence of such functional modulations remains unknown. Also, the signal-altering mechanisms by which AS, and PTMs modulate function and the extent to which AS and PTMs collaborate in their signaling modulations have not been well defined for particular protein examples. Here we focus on three important signaling and regulatory IDR-containing protein families in humans, namely, G protein-coupled receptors (GPCRs), which are transmembrane proteins;the nuclear factors of activated T cells (NFATs), which are transcription factors;and the Src family kinases (SFKs), which are signaling enzymes. The goals here are to determine how AS and PTMs individually alter the outcomes of the signaling carried out by the various IDRs and to determine whether AS and PTMs work together to bring about differential cellular responses. We also present data indicating that a wide range of other signaling IDPs or IDRs undergo both AS- and PTM-based modifications, suggesting that they, too, likely take advantage of signal outcome modulations that result from collaboration between these two events. Hence, we propose that the widespread cooperation of IDPs, AS and/or PTMs provides an IDP-AS-PTM toolkit and substantially contributes to the vast complexity of eukaryotic cell signaling systems. (C) 2018 Elsevier Ltd. All rights reserved.

关键词： intrinsic disorder alternative splicing post-translational modification differential and context-dependent signaling signaling modulation and regulation

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基于PFC3D的新建下穿隧道对既有隧道的影响分析

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水力发电 2022年第3期48卷 43-47页

作者：黄春峰赵苏文孙淼军邱烈望上海铁路枢纽建设指挥部上海200071 中国电建集团华东勘测设计研究院有限公司浙江杭州311122 浙江华东建设工程有限公司浙江杭州310010 新疆大学建筑工程学院新疆乌鲁木齐830046

采用离散元PFC3D软件建立模型,以乌鲁木齐地铁河南路段区间工程为例,模拟分析新建下穿隧道对既有隧道的影响。结果表明,既有隧道上方竖向位移和竖向应力受新建隧道开挖影响较小,隧道左右两侧3.75 m处竖向位移和水平应力产生突变;新建隧... 详细信息

采用离散元PFC3D软件建立模型,以乌鲁木齐地铁河南路段区间工程为例,模拟分析新建下穿隧道对既有隧道的影响。结果表明,既有隧道上方竖向位移和竖向应力受新建隧道开挖影响较小,隧道左右两侧3.75 m处竖向位移和水平应力产生突变;新建隧道与既有隧道之间,在近既有隧道区域竖向位移和竖向应力产生较大变化,而新建隧道区域竖向位移和竖向应力变化较小;新建隧道底部竖向位移和竖向应力产生较大变化,新建隧道左右两侧竖向位移和水平应力在3.75 m处产生较大变化。

关键词：隧道工程正交下穿位移应力数值模拟颗粒流PFC

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水下井口及配套工具压力测试工装设计与分析

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海洋工程装备与技术 2023年第2期10卷 14-21页

作者：耿亚楠王名春孙翀张会增赵维青赵苏文李健胡晓宇中海油研究总院有限责任公司北京100028 中海油能源发展股份有限公司工程技术深水钻采技术公司广东湛江524057 中国石油大学海洋油气装备与安全技术研究中心山东青岛266580

水下井口是深水油气钻井作业的关键装备,承受复杂多变的内压和外部载荷。目前,主要通过理论分析和数值模拟的方法,对水下井口进行强度分析。但缺乏水下井口压力测试的专用测试工装,无法真实反映水下井口系统及其配套工具承压作业时的安... 详细信息

水下井口是深水油气钻井作业的关键装备,承受复杂多变的内压和外部载荷。目前,主要通过理论分析和数值模拟的方法,对水下井口进行强度分析。但缺乏水下井口压力测试的专用测试工装,无法真实反映水下井口系统及其配套工具承压作业时的安全性。针对此问题,本文考虑水下井口系统作业过程中的不同作业工况,针对水下井口不同作业阶段的内压载荷,分别设计了相应的专用测试工装。为保证工装结构的测试稳定性,采用有限元分析方法,建立测试工装有限元模型,开展了不同测试载荷下工装结构的力学响应分析。分析结果表明,水下井口专用测试工装能够开展不同作业阶段的承压能力测试,在测试过程中,工装结构各部件应力均未超出材料屈服强度。本研究可为水下井口测试工装的结构设计和优化分析提供技术支持。

关键词：水下井口压力测试工装强度分析 Ansys Workbench

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Structural insights into the activation of chemokine receptor CXCR2

Structural insights into the activation of chemokine recepto...

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第七届全国冷冻电子显微学与结构生物学专题研讨会

作者：刘凯雯 Lijie Wu Shuguang Yuan Meng Wu Yueming Xu Qianqian Sun Shu Li suwen zhao Tian Hua Zhi-Jie Liu iHuman Institute ShanghaiTech University School of Life Science and Technology ShanghaiTech University University of Chinese Academy of Sciences Institute of Biochemistry and Cell Biology Shanghai Institutes for Biological Science The Research Center for Computer-aided Drug Discovery Shenzhen Institutes of Advanced Technology

＜正＞Chemokines and their receptors mediate cell migration which influences multiple fundamental biological processes and disease conditions,such as inflammation and ***,we report the cryo-electron microscopy structures of interleukin-8 （IL8,also known as CXCL8） activated human CXC chemokine receptor 2 （CXCR2） in complex with Gi protein,along with a designed allosteric antagonist-bound CXCR2 crystal *** results uncover a unique shallow binding mode between CXCL8 and CXCR2,as well as CXCR2-Gi protein interactions.

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A unique hormonal recognition feature of the human glucagon-like peptide-2 receptor

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细胞研究（英文版） 2020年第12期30卷 1098-1108页

作者： Wen Sun Li-Nan Chen Qingtong Zhou Li-Hua zhao Dehua Yang Huibing Zhang zhaotong Cong Dan-Dan Shen Fenghui zhao Fulai Zhou Xiaoqing Cai Yan Chen Yan Zhou Sarina Gadgaard Wijnand J. C. van der Velden suwen zhao Yi Jiang Mette M. Rosenkilde H. Eric Xu Yan Zhang Ming-Wei Wang The CAS Key Laboratory of Receptor Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China The National Center for Drug Screening Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China University of Chinese Academy of Sciences Beijing 100049 China Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310058 China iHuman Institute ShanghaiTech University Shanghai 201210 China School of Basic Medical Sciences Fudan University Shanghai 200032 China The CAS Key Laboratory of Receptor Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China The CAS Key Laboratory of Receptor Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China The National Center for Drug Screening Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310058 China School of Pharmacy Fudan UniversityShanghai 201203 China Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310058 China School of Pharmacy Fudan UniversityShanghai 201203 China The CAS Key Laboratory of Receptor Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China The National Center for Drug Screening Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China The CAS Key Laboratory of Receptor Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China The National Center for Drug Screening Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China School of Pharmacy Fudan UniversityShanghai 201203 China

Glucagon-like peptides(GLP-1 and GLP-2)are two proglucagon-derived intestinal hormones that mediate distinct physiological functions through two related receptors(GLP-1 R and GLP-2R)which are important drug targets for metabolic disorders and Crohn's disease,*** great progress in GLP-1 R structure determination,our understanding on the differences of peptide binding and signal transduction between these two receptors remains *** we report the electron microscopy structure of the human GLP-2R in complex with GLP-2 and a Gs *** accommodate GLP-2 rather than GLP-1,GLP-2R fine-tunes the conformations of the extracellular parts of transmembrane helices(TMs)1,5,7 and extracellular loop 1(ECL1).In contrast to GLP-1,the N-terminal histidine of GLP-2 penetrates into the receptor core with a unique *** middle region of GLP-2 engages with TM1 and TM7 more extensively than with ECL2,and the GLP-2 C-terminus closely attaches to ECL1,which is the most protruded among 9 class B G protein-coupled receptors(GPCRs).Functional studies revealed that the above three segments of GLP-2 are essential for GLP-2 recognition and receptor activation,especially the middle *** results provide new insights into the molecular basis of ligand specificity in class B GPCRs and may facilitate the development of more specific therapeutics.

关键词： Cryoelectron microscopy Hormone receptors

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G蛋白偶联受体的共同激活机制

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自然杂志 2021年第1期43卷 45-52页

作者：周庆同戴之卓赵素文复旦大学基础医学院上海200032 上海科技大学iHuman研究所上海201210 上海科技大学生命科学与技术学院上海201210

G蛋白偶联受体(G protein-coupled receptor,GPCR)构成人体中最庞大的膜蛋白家族,也是最重要的一类药物靶标。随着GPCR结构解析技术的突破,目前已破解八十余个受体的400多个结构,揭示出GPCR复杂多样的配体结合模式和跨膜信号转导机制。... 详细信息

G蛋白偶联受体(G protein-coupled receptor,GPCR)构成人体中最庞大的膜蛋白家族,也是最重要的一类药物靶标。随着GPCR结构解析技术的突破,目前已破解八十余个受体的400多个结构,揭示出GPCR复杂多样的配体结合模式和跨膜信号转导机制。近年来,残基相互作用计算已实现对GPCR构象变化的精细描述,揭示出A家族GPCR存在共同的激活机制。文章简要回顾GPCR激活机制研究的方法和创新点,并对A家族GPCR共同激活机制如何推动功能研究和药物研发进行展望。

关键词： G蛋白偶联受体激活机制别构调控药物开发

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The chordata olfactory receptor database

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Protein & Cell 2025年第4期 283-292页

作者： Wei Han Siyu Bao Jintao Liu Yiran Wu Liting Zeng Tao Zhang Ningmeng Chen Kai Yao Shunguo Fan Aiping Huang Yuanyuan Feng Guiquan Zhang Ruiyi Zhang Hongjin Zhu Tian Hua Zhijie Liu Lina Cao Xingxu Huang suwen zhao iHuman Institute Shanghai Tech University Research Center for Life Sciences Computing Zhejiang Lab Department of Intelligent Edge Cloud China Telecom Cloud Technology Co. Ltd. School of Life Science and Technology Shanghai Tech University School of Information Science and Technology Shanghai Tech University Shanghai Key Laboratory of High-Resolution Electron Microscopy Shanghai Tech University Zhejiang Provincial Key Laboratory of Pancreatic Disease The First Affiliated Hospital and Institute of Translational Medicine Zhejiang University School of Medicine Shanghai Clinical Research and Trial Center

Introduction of database Olfaction is one of the oldest chemosensory systems in chordates, playing crucial roles in their foraging, predator evasion, social communication, mating and parental care (Guo et al., 2023; Li and Liberles, 2015; Liberles,2014). The initial step of olfaction is the binding and activation of olfactory receptors (ORs) by odorants in a combinatorial way (Malnic et al., 1999).

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Structural basis of ligand recognition and self-activation of orphan GPR52

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NATURE 2020年第7797期579卷 152-+页

作者： Lin, Xi Li, Mingyue Wang, Niandong Wu, Yiran Luo, Zhipu Guo, Shimeng Han, Gye-Won Li, Shaobai Yue, Yang Wei, Xiaohu Xie, Xin Chen, Yong zhao, suwen Wu, Jian Lei, Ming Xu, Fei ShanghaiTech Univ iHuman Inst Shanghai Peoples R China ShanghaiTech Univ Sch Life Sci & Technol Shanghai Peoples R China Chinese Acad Sci Shanghai Inst Biol Sci Inst Biochem & Cell Biol Shanghai Peoples R China Univ Chinese Acad Sci Beijing Peoples R China Soochow Univ Sch Biol & Basic Med Sci Inst Mol Enzymol Suzhou Peoples R China Chinese Acad Sci Shanghai Inst Mat Med Natl Ctr Drug Screening CAS Key Lab Receptor Res Shanghai Peoples R China Univ Southern Calif Bridge Inst Dept Biol Sci Los Angeles CA USA Shanghai Jiao Tong Univ Peoples Hosp 9 Sch Med Shanghai Peoples R China Shanghai Inst Precis Med Shanghai Peoples R China Shanghai Key Lab Translat Med Ear & Nose Dis Shanghai Peoples R China Shanghai Jiao Tong Univ Sch Med Chinese Minist Educ Key Lab Cell Differentiat & Apoptosis Shanghai Peoples R China Chinese Acad Sci Ctr Excellence Mol Cell Sci Shanghai Peoples R China

Structures of the orphan G-protein-coupled receptor GPR52 in ligand-free, G-protein-coupled and ligand-bound states reveal that extracellular loop 2 occupies the orthosteric binding pocket and functions as a built-in agonist to activate the receptor. GPR52 is a class-A orphan G-protein-coupled receptor that is highly expressed in the brain and represents a promising therapeutic target for the treatment of Huntington's disease and several psychiatric disorders(1,2). Pathological malfunction of GPR52 signalling occurs primarily through the heterotrimeric G(s) protein(2), but it is unclear how GPR52 and G(s) couple for signal transduction and whether a native ligand or other activating input is required. Here we present the high-resolution structures of human GPR52 in three states: a ligand-free state, a G(s)-coupled self-activation state and a potential allosteric ligand-bound state. Together, our structures reveal that extracellular loop 2 occupies the orthosteric binding pocket and operates as a built-in agonist, conferring an intrinsically high level of basal activity to GPR52(3). A fully active state is achieved when G(s) is coupled to GPR52 in the absence of an external agonist. The receptor also features a side pocket for ligand binding. These insights into the structure and function of GPR52 could improve our understanding of other self-activated GPCRs, enable the identification of endogenous and tool ligands, and guide drug discovery efforts that target GPR52.

关键词： Drug discovery Electron microscopy X-ray crystallography

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The structure-based traceless specific fluorescence labeling of the smoothened receptor

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ORGANIC & BIOMOLECULAR CHEMISTRY 2019年第25期17卷 6136-6142页

作者： Xue, Dongxiang Ye, Lintao Zheng, Jun Wu, Yiran Zhang, Xianjun Xu, Yueming Li, Tao Stevens, Raymond C. Xu, Fei Zhuang, Min zhao, suwen zhao, Fei Tao, Houchao ShanghaiTech Univ iHuman Inst Ren Bldg393 Middle Huaxia Rd Shanghai 201210 Peoples R China Chinese Acad Sci Shanghai Inst Mat Med 555 Zuchongzhi RdBldg 3Room 426 Shanghai 201203 Peoples R China Univ Chinese Acad Sci 19A Yuquan Rd Beijing 100049 Peoples R China ShanghaiTech Univ Sch Life Sci & Technol Shanghai 201210 Peoples R China

The smoothened receptor (SMO) mediates the hedgehog (Hh) signaling pathway and plays a vital role in embryonic development and tumorigenesis. The visualization of SMO has the potential to provide new insights into its enigmatic mechanisms and associated disease pathogenesis. Based on recent progress in structural studies of SMO, we have designed and characterized a group of affinity probes to facilitate the turn-on fluorescence labeling of SMO at the epsilon-amine of K395. These chemical probes were derived from a potent SMO antagonist skeleton by the conjugation of a small non-fluorescent unit, O-nitrobenzoxadiazole (O-NBD). In this context, optimal probes were developed to be capable of efficiently and selectively lighting up SMO regardless of whether it is in micelles or in native membranes. More importantly, the resulting labeled SMO only bears a very small fluorophore and allows for the recovery of the unoccupied pocket by dissociation of the residual ligand module. These advantages should allow the probe to serve as a potential tool for monitoring SMO trafficking, understanding Hh activation mechanisms, and even the diagnosis of tumorigenesis in the future.

关键词： Probes

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Colocalization Strategy Unveils an Underside Binding Site in the Transmembrane Domain of Smoothened Receptor

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JOURNAL OF MEDICINAL CHEMISTRY 2019年第21期62卷 9983-9989页

作者： Zhou, Fang Ding, Kang Zhou, Yiqing Liu, Yang Liu, Xiaoyan zhao, Fei Wu, Yiran Zhang, Xianjun Tan, Qiwen Xu, Fei Tan, Wenfu Xiao, Youli zhao, suwen Tao, Houchao ShanghaiTech Univ iHuman Inst Ren Bldg393 Middle Huaxia Rd Shanghai 201210 Peoples R China Chinese Acad Sci Shanghai Inst Materia Med 555 Zuchongzhi RdBldg 3Room 426 Shanghai 201203 Peoples R China Chinese Acad Sci CAS MPG Partner Inst Computat Biol Shanghai Inst Biol Sci Key Lab Computat Biol Shanghai 200031 Peoples R China Chinese Acad Sci Shanghai Inst Biol Sci Inst Plant Physiol & Ecol CAS Key Lab Synthet Biol Shanghai 200032 Peoples R China Univ Chinese Acad Sci 19A Yuquan Rd Beijing 100049 Peoples R China ShanghaiTech Univ Sch Life Sci & Technol Shanghai 201210 Peoples R China Fudan Univ Sch Pharm Dept Pharmacol Shanghai 201203 Peoples R China Chinese Acad Sci Shanghai Inst Biol Sci Inst Biochem & Cell Biol Shanghai 200031 Peoples R China Changshu Inst Technol Sch Biotechnol & Food Engn Suzhou 215500 Jiangsu Peoples R China

We unveiled an underside binding site on smoothened receptor (SMO) by a colocalization strategy using two structurally complementary photoaffinity probes derived from a known ligand Allo-1. Docking study and structural dissection identified key interactions within the site, including hydrogen bonding, pi-pi interactions, and hydrophobic interactions between Allo-1 and its contacting residues. Taken together, our results reveal the molecular base of Allo-1 binding and provide a basis for the design of new-generation ligands to overcome drug resistance.

关键词： Soil organic matter Hydrocarbons Aromatic compounds Screening assays Probes

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