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第十六次中国暨国际生物物理大会

作者： Dazhi Liu Yifeng Wei Xuyang Liu Yan Zhou Li Jiang Jinyu Yin Feifei Wang Yiling Hu Ankanahalli N Nanjaraj Urs Yanhong Liu Ee Lui Ang suwen zhao Huimin zhao Yan Zhang Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency Collaborative Innovation Center of Chemical Science and EngineeringSchool of Pharmaceutical Science and TechnologyTianjin University Metabolic Engineering Research Laboratory Institute of Chemical and Engineering SciencesAgency for ScienceTechnology and Research(A~*STAR) iHuman Institute ShanghaiTech University School of Life Science and Technology ShanghaiTech University Technical Institute of Physics and Chemistry Chinese Academy of Sciences Department of Chemical and Biomolecular Engineering University of Illinois at Urbana-Champaign600 South Mathews Avenue

Skatole is a malodorous compound that contributes to the characteristic smell of animal faeces. Although skatole has long been known to originate from bacterial tryptophan fermentation, the enzyme catalysing its formation has so far remained elusive. Here we report the use of comparative genomics for the discovery of a new O2-sensitive glycyl radical enzyme catalysing the decarboxylation of indoleacetate to form skatole,

关键词： Indoleacetate decarboxylase a new glycyl radical enzyme catalysing the formation of malodorant skatole

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Activation and Signaling Mechanism Revealed by Cannabinoid Receptor-Gi Complex Structures

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CELL 2020年第4期180卷 655-+页

作者： Hua, Tian Li, Xiaoting Wu, Lijie Iliopoulos-Tsoutsouvas, Christos Wang, Yuxia Wu, Meng Shen, Ling Brust, Christina A. Nikas, Spyros P. Song, Feng Song, Xiyong Yuan, Shuguang Sun, Qianqian Wu, Yiran Jiang, Shan Grim, Travis W. Benchama, Othman Stahl, Edward L. Zvonok, Nikolai zhao, suwen Bohn, Laura M. Makriyannis, Alexandros Liu, Zhi-Jie ShanghaiTech Univ iHuman Inst Shanghai 201210 Peoples R China Northeastern Univ Ctr Drug Discovery Boston MA 02115 USA Northeastern Univ Dept Pharmaceut Sci Boston MA 02115 USA ShanghaiTech Univ Sch Life Sci & Technol Shanghai 201210 Peoples R China Scripps Res Dept Mol Med Jupiter FL 33458 USA Scripps Res Dept Neurosci Jupiter FL 33458 USA Dezhou Univ Sch Life Sci Dezhou 253023 Shandong Peoples R China Kunming Med Univ Inst Mol & Clin Med Kunming 650500 Yunnan Peoples R China Chinese Acad Sci Shenzhen Inst Adv Technol Res Ctr Comp Aided Drug Discovery Shenzhen 518055 Peoples R China Northeastern Univ Dept Chem Boston MA 02115 USA Northeastern Univ Dept Biol Chem Boston MA 02115 USA

Human endocannabinoid systems modulate multiple physiological processes mainly through the activation of cannabinoid receptors CB1 and CB2. Their high sequence similarity, low agonist selectivity, and lack of activation and G protein-coupling knowledge have hindered the development of therapeutic applications. Importantly, missing structural information has significantly held back the development of promising CB2-selective agonist drugs for treating inflammatory and neuropathic pain without the psychoactivity of CB1. Here, we report the cryoelectron microscopy structures of synthetic cannabinoid-bound CB2 and CB1 in complex with G(i), as well as agonist-bound CB2 crystal structure. Of important scientific and therapeutic benefit, our results reveal a diverse activation and signaling mechanism, the structural basis of CB2-selective agonists design, and the unexpected interaction of cholesterol with CB1, suggestive of its endogenous allosteric modulating role.

关键词： G protein-coupled receptor cannabinoid receptors cryo-EM structures CB2-Gi crystal structure activation subtype selectivity allosteric modulation cholesterol

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Crystal structures of agonist-bound human cannabinoid receptor CB₁

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NATURE 2017年第7664期547卷 468-+页

作者： Hua, Tian Vemuri, Kiran Nikas, Spyros P. Laprairie, Robert B. Wu, Yiran Qu, Lu Pu, Mengchen Korde, Anisha Jiang, Shan Ho, Jo-Hao Han, Gye Won Ding, Kang Li, Xuanxuan Liu, Haiguang Hanson, Michael A. zhao, suwen Bohn, Laura M. Makriyannis, Alexandros Stevens, Raymond C. Liu, Zhi-Jie 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 Northeastern Univ Dept Pharmaceut Sci Ctr Drug Discovery Boston MA 02115 USA Northeastern Univ Dept Chem & Chem Biol Boston MA 02115 USA Scripps Res Inst Dept Mol Med Jupiter FL 33458 USA Scripps Res Inst Dept Neurosci Jupiter FL 33458 USA Univ Southern Calif Bridge Inst Dept Biol Sci Los Angeles CA 90089 USA Univ Southern Calif Bridge Inst Dept Chem Los Angeles CA 90089 USA ShanghaiTech Univ Sch Life Sci & Technol Shanghai 201210 Peoples R China Beijing Computat Sci Res Ctr Complex Syst Div Beijing 100193 Peoples R China GPCR Consortium San Marcos CA 92078 USA

The cannabinoid receptor 1 (CB1) is the principal target of the psychoactive constituent of marijuana, the partial agonist Delta(9)-tetrahydrocannabinol (Delta(9)-THC)(1). Here we report two agonist-bound crystal structures of human CB1 in complex with a tetrahydrocannabinol (AM11542) and a hexahydrocannabinol (AM841) at 2.80 angstrom and 2.95 angstrom resolution, respectively. The two CB1-agonist complexes reveal important conformational changes in the overall structure, relative to the antagonist-bound state(2), including a 53% reduction in the volume of the ligand-binding pocket and an increase in the surface area of the G-protein-binding region. In addition, a 'twin toggle switch' of Phe200(3.36) and Trp356(6.48) (superscripts denote Ballesteros-Weinstein numbering(3)) is experimentally observed and appears to be essential for receptor activation. The structures reveal important insights into the activation mechanism of CB1 and provide a molecular basis for predicting the binding modes of Delta(9)-THC, and endogenous and synthetic cannabinoids. The plasticity of the binding pocket of CB1 seems to be a common feature among certain class A G-protein-coupled receptors. These findings should inspire the design of chemically diverse ligands with distinct pharmacological properties.

关键词： X-ray crystallography Cell signalling Structure-based drug design

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Determination of the melanocortin-4 receptor structure identifies Ca²⁺ as a cofactor for ligand binding

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SCIENCE 2020年第6489期368卷 428-+页

作者： Yu, Jing Gimenez, Luis E. Hernandez, Ciria C. Wu, Yiran Wein, Ariel H. Han, Gye Won McClary, Kyle Mittal, Sanraj R. Burdsall, Kylie Stauch, Benjamin Wu, Lijie Stevens, Sophia N. Peisley, Alys Williams, Savannah Y. Chen, Valerie Millhauser, Glenn L. zhao, suwen Cone, Roger D. Stevens, Raymond C. ShanghaiTech Univ IHuman Inst Shanghai 201210 Peoples R China ShanghaiTech Univ Sch Life Sci & Technol Shanghai 201210 Peoples R China Univ Chinese Acad Sci CAS Ctr Excellence Mol Cell Sci Shanghai Inst Biochem & Cell Biol Chinese Acad Sci Shanghai 200031 Peoples R China Univ Michigan Life Sci Inst Ann Arbor MI 48109 USA Univ Southern Calif Dept Biol Sci Bridge Inst USC Michelson Ctr Convergent Biosci Los Angeles CA 90089 USA Univ Southern Calif Dept Chem Bridge Inst USC Michelson Ctr Convergent Biosci Los Angeles CA 90089 USA Univ Calif Santa Cruz Dept Chem & Biochem Santa Cruz CA 95064 USA Univ Michigan Sch Med Dept Mol & Integrat Physiol Ann Arbor MI 48109 USA

The melanocortin-4 receptor (MC4R) is involved in energy homeostasis and is an important drug target for syndromic obesity. We report the structure of the antagonist SHU9119-bound human MC4R at 2.8-angstrom resolution. Ca2+ is identified as a cofactor that is complexed with residues from both the receptor and peptide ligand. Extracellular Ca2+ increases the affinity and potency of the endogenous agonist alpha-melanocyte-stimulating hormone at the MC4R by 37- and 600-fold, respectively. The ability of the MC4R crystallized construct to couple to ion channel Kir7.1, while lacking cyclic adenosine monophosphate stimulation, highlights a heterotrimeric GTP-binding protein (G protein)-independent mechanism for this signaling modality. MC4R is revealed as a structurally divergent G protein-coupled receptor (GPCR), with more similarity to lipidic GPCRs than to the homologous peptidic GPCRs.

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深水油气井测试作业时环空压力预测及安全评价

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中国安全生产科学技术 2023年第9期19卷 110-115页

作者：庞东豪赵维青赵苏文唐龙向世林张智周驰宇敬耘博中海油能源发展股份有限公司工程技术分公司天津塘沽300450 西南石油大学油气藏地质及开发工程国家重点实验室四川成都610500 西南石油大学计算机科学学院四川成都610500

为准确预测深水高温高压油气井测试作业时,密闭及非密闭环空压力的变化规律,基于流体温压性质的变化规律,综合考虑流体温度、环空体积、流体质量变化,建立密闭及非密闭环空压力预测模型,研究不同变化因素对环空压力预测结果的影响。研... 详细信息

为准确预测深水高温高压油气井测试作业时,密闭及非密闭环空压力的变化规律,基于流体温压性质的变化规律,综合考虑流体温度、环空体积、流体质量变化,建立密闭及非密闭环空压力预测模型,研究不同变化因素对环空压力预测结果的影响。研究结果表明:充分考虑流体温压性质变化和流体质量变化影响后的环空压力预测结果更为准确;非密闭环空可以有效缓解持续上升的环空压力。研究结果可为深水油气井测试作业时,有效提升井筒管柱及屏障的完整性与安全提供一定参考。

关键词：深水井环空压力密闭环空非密闭环空流体温压性质变化流体质量变化

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Correction to "A Novel G Protein-Biased and Subtype-Selective Agonist for a G Protein-Coupled Receptor Discovered from Screening Herbal Extracts"

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ACS central science 2020年第5期6卷 823-824页

作者： Bingjie Zhang Simeng zhao Dehua Yang Yiran Wu Ye Xin Haijie Cao Xi-Ping Huang Xiaoqing Cai Wen Sun Na Ye Yueming Xu Yao Peng suwen zhao Zhi-Jie Liu Guisheng Zhong Ming-Wei Wang Wenqing Shui

[This corrects the article DOI: 10.1021/acscentsci.9b01125.].

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水下井口连接器密封性能影响因素分析与优化

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石油机械 2022年第7期50卷 86-91页

作者：刘书杰孟文波黄熠刘和兴李磊黄亮赵苏文中海石油(中国)有限公司湛江分公司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

水下井口连接器作为连接高压井口与水下采油树、防止井内高温高压流体泄漏的关键设备,其承受着极其恶劣的载荷作用。为研究内压工况下流体渗透压力对井口连接器金属-金属密封的影响,以自主研制的井口连接器为对象,考虑流体渗透压力对VX... 详细信息

水下井口连接器作为连接高压井口与水下采油树、防止井内高温高压流体泄漏的关键设备,其承受着极其恶劣的载荷作用。为研究内压工况下流体渗透压力对井口连接器金属-金属密封的影响,以自主研制的井口连接器为对象,考虑流体渗透压力对VX钢圈密封性能的影响,运用ABAQUS软件分析了井口连接器在预紧和内压工况下的密封性能,探究了预紧力、介质压力、密封圈材料性能和结构参数对其接触应力的影响规律。研究结果表明:轴向预紧力是影响连接器密封性能的重要因素,在保证连接器结构强度下应尽量增大预紧力;随着内压的增大,上密封面的接触应力增加,趋势与下密封面相比较增加速率变低,且下密封面接触应力大于上密封面;316L不锈钢满足密封准则,用其作为密封圈材料更为经济;最优密封锥面锥角α为22.75°,最优密封面宽度b_(0)为28 mm。所得结论可为其他类型水下井口连接器的密封结构设计提供依据。

关键词：井口连接器 VX钢圈金属-金属密封渗透压力轴向预紧力

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Virus Disinfection from Environmental Water Sources Using Living Engineered Biofilm Materials

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ADVANCED SCIENCE 2020年第14期7卷 1903558页

作者： Pu, Jiahua Liu, Yi Zhang, Jicong An, Bolin Li, Yingfeng Wang, Xinyu Din, Kang Qin, Chong Li, Ke Cui, Mengkui Liu, Suying Huang, Yuanyuan Wang, Yanyi Lv, Yanan Huang, Jiaofang Cui, Zongqiang zhao, suwen Zhong, Chao ShanghaiTech Univ Sch Phys Sci & Technol Mat & Phys Biol Div 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 Wuhan Inst Virol State Key Lab Virol Wuhan 430071 Peoples R China Wuxi Biol Co Ltd Suzhou 215100 Peoples R China Chinese Acad Sci Shanghai Inst Appl Phys Shanghai 201800 Peoples R China Chinese Acad Sci Mat Synthet Biol Ctr Shenzhen Inst Synthet Biol Shenzhen Inst Adv Technol Shenzhen 518055 Peoples R China Chinese Acad Sci Shenzhen Inst Synthet Biol Shenzhen Inst Adv Technol CAS Key Lab Quantitat Engn Biol Shenzhen 518055 Guangdong Peoples R China

Waterborne viruses frequently cause disease outbreaks and existing strategies to remove such viral pathogens often involve harsh or energy-consuming water treatment processes. Here, a simple, efficient, and environmentally friendly approach is reported to achieve highly selective disinfection of specific viruses with living engineered biofilm materials. As a proof-of-concept, Escherichia coli biofilm matrix protein CsgA was initially genetically fused with the influenza-virus-binding peptide (C5). The resultant engineered living biofilms could correspondingly capture virus particles directly from aqueous solutions, disinfecting samples to a level below the limit-of-detection for a qPCR-based detection assay. By exploiting the surface-adherence properties of biofilms, it is further shown that polypropylene filler materials colonized by the CsgA-C5 biofilms can be utilized to disinfect river water samples with influenza titers as high as 1 x 10(7) PFU L-1. Additionally, a suicide gene circuit is designed and applied in the engineered strain that strictly limits the growth of bacterial, therefore providing a viable route to reduce potential risks confronted with the use of genetically modified organisms. The study thus illustrates that engineered biofilms can be harvested for the disinfection of pathogens from environmental water samples in a controlled manner and highlights the unique biology-only properties of living substances for material applications.

关键词： engineered biofilms living materials water disinfection

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Crystal Structure of the Human Cannabinoid Receptor CB2

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CELL 2019年第3期176卷 459-+页

作者： Li, Xiaoting Hua, Tian Vemuri, Kiran Ho, Jo-Hao Wu, Yiran Wu, Lijie Popov, Petr Benchama, Othman Zvonok, Nikolai Locke, K'ara Qu, Lu Han, Gye Won Iyer, Malliga R. Cinar, Resat Coffey, Nathan J. Wang, Jingjing Wu, Meng Katritch, Vsevolod zhao, suwen Kunos, George Bohn, Laura M. Makriyannis, Alexandros Stevens, Raymond C. Liu, Zhi-Jie ShanghaiTech Univ iHuman Inst Shanghai 201210 Peoples R China ShanghaiTech Univ Sch Life Sci & Technol Shanghai 201210 Peoples R China Chinese Acad Sci Shanghai Inst Biol Sci Inst Biochem & Cell Biol Shanghai Peoples R China Univ Chinese Acad Sci Beijing 100049 Peoples R China Northeastern Univ Dept Chem & Chem Biol Ctr Drug Discovery Boston MA 02115 USA Northeastern Univ Dept Pharmaceut Sci Boston MA 02115 USA Scripps Res Dept Mol Med Jupiter FL 33458 USA Univ Southern Calif Bridge Inst Dept Biol Sci Los Angeles CA 90089 USA NIAAA Lab Physiol Studies NIH Bethesda MD 20892 USA Moscow Inst Phys & Technol Dolgoprudnyi Russia Skolkovo Inst Sci & Technol Moscow Russia

The cannabinoid receptor CB2 is predominately expressed in the immune system, and selective modulation of CB2 without the psychoactivity of CB1 has therapeutic potential in inflammatory, fibrotic, and neurodegenerative diseases. Here, we report the crystal structure of human CB2 in complex with a rationally designed antagonist, AM10257, at 2.8 angstrom resolution. The CB2-AM10257 structure reveals a distinctly different binding pose compared with CB1. However, the extracellular portion of the antagonist-bound CB2 shares a high degree of conformational similarity with the agonist-bound CB1, which led to the discovery of AM10257's unexpected opposing functional profile of CB2 antagonism versus CB1 agonism. Further structural analysis using mutagenesis studies and molecular docking revealed the molecular basis of their function and selectivity for CB2 and CB1. Additional analyses of our designed antagonist and agonist pairs provide important insight into the activation mechanism of CB2. The present findings should facilitate rational drug design toward precise modulation of the endocannabinoid system.

关键词： G-protein coupled receptor cannabinoid receptor CB2 crystal structure ligand design subtype selectivity

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Experimental Strategies for Functional Annotation and Metabolism Discovery: Targeted Screening of Solute Binding Proteins and Unbiased Panning of Metabolomes

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BIOCHEMISTRY 2015年第3期54卷 909-931页

作者： Vetting, Matthew W. Al-Obaidi, Nawar zhao, suwen San Francisco, Brian Kim, Jungwook Wichelecki, Daniel J. Bouvier, Jason T. Solbiati, Jose O. Hoan Vu Zhang, Xinshuai Rodionov, Dmitry A. Love, James D. Hillerich, Brandan S. Seidel, Ronald D. Quinn, Ronald J. Osterman, Andrei L. Cronan, John E. Jacobson, Matthew P. Gerlt, John A. Almo, Steven C. Albert Einstein Coll Med Dept Biochem Bronx NY 10461 USA Univ Calif San Francisco Dept Pharmaceut Chem San Francisco CA 94158 USA Univ Illinois Inst Genom Biol Urbana IL 61801 USA Univ Illinois Dept Biochem Urbana IL 61801 USA Univ Illinois Dept Chem Urbana IL 61801 USA Univ Illinois Dept Microbiol Urbana IL 61801 USA Griffith Univ Eskitis Inst Drug Discovery Brisbane Qld 4111 Australia Sanford Burnham Med Res Inst La Jolla CA 92037 USA Russian Acad Sci AA Kharkevich Inst Informat Transmiss Problems Moscow 127994 Russia

The rate at which genome sequencing data is accruing demands enhanced methods for functional annotation and metabolism discovery. Solute binding proteins (SBPs) facilitate the transport of the first reactant in a metabolic pathway, thereby constraining the regions of chemical space and the chemistries that must be considered for pathway reconstruction. We describe high-throughput protein production and differential scanning fluorimetry platforms, which enabled the screening of 158 SBPs against a 189 component library specifically tailored for this class of proteins. Like all screening efforts, this approach is limited by the practical constraints imposed by construction of the library, i.e., we can study only those metabolites that are known to exist and which can be made in sufficient quantities for experimentation. To move beyond these inherent limitations, we illustrate the promise of crystallographic- and mass spectrometric-based approaches for the unbiased use of entire metabolomes as screening libraries. Together, our approaches identified 40 new SBP ligands, generated experiment-based annotations for 2084 SBPs in 71 isofunctional clusters, and defined numerous metabolic pathways, including novel catabolic pathways for the utilization of ethanolamine as sole nitrogen source and the use of D-Ala-D-Ala as sole carbon source. These efforts begin to define an integrated strategy for realizing the full value of amassing genome sequence data.

关键词： Bacillus/metabolism Carbohydrates/chemistry Carrier Proteins/metabolism Cloning, Molecular Crystallography, X-Ray Fluorometry Kinetics Ligands Metabolic Networks and Pathways Metabolome Metabolomics/methods Molecular Sequence Annotation Reproducibility of Results Sequence Homology, Amino Acid

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