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| 1 | Design and development of an oral remdesivir derivative W116 against SARS-CoV-2显示文摘Dear Editor,Since the declaration of COVID-19 as a global pandemic on March 11,2020,this pandemic has been circulating for 17 months throughout the world,leading to more than 200 million infections and nearly 4.4 million deaths as of August 15,2021.The pathogen of COVID-19 is a novel coronavirus named SARS-CoV-2,which shares-79%genome sequence identity with SARS-CoV.1 At the early stage of the COVID-19 outbreak,5ARS-CoV-2 caused great panic in the hardest-hit areas due to its high transmissibility and pathogenicity.To fight the COVID-19 crisis,drug repurposing was immediately pursued in order to find potential therapeutics. | Yuanchao Xie Wanchao Yin Yumin Zhang Weijuan Shang Zhen Wang Xiaodong Luan Guanghui Tian Haji A.Aisa Yechun Xu Gengfu Xiao Jia Li Hualiang Jiang Shuyang Zhanq Leike Zhang H.Eric Xu Jingshan Shen | 2021 | Cell Research2021，31，11： | 12 |
| 2 | Structural and biochemical mechanism for increased infectivity and immune evasion of Omicron BA.2 variant compared to BA.1 and their possible mouse origins显示文摘The Omicron BA.2 variant has become a dominant infective strain worldwide.Receptor binding studies show that the Omicron BA.2 spike trimer exhibits 11-fold and 2-fold higher potency in binding to human ACE2 than the spike trimer from the wildtype(WT)and Omicron BA.1 strains.The structure of the BA.2 spike trimer complexed with human ACE2 reveals that all three receptor-binding domains(RBDs)in the spike trimer are in open conformation,ready for ACE2 binding,thus providing a basis for the increased infectivity of the BA.2 strain.JMB2002,a therapeutic antibody that was shown to efficiently inhibit Omicron BA.1,also shows potent neutralization activities against Omicron BA.2.In addition,both BA.1 and BA.2 spike trimers are able to bind to mouse ACE2 with high potency.In contrast,the WT spike trimer binds well to cat ACE2 but not to mouse ACE2.The structures of both BA.1 and BA.2 spike trimer bound to mouse ACE2 reveal the basis for their high affinity interactions.Together,these results suggest a possible evolution pathway for Omicron BA.1 and BA.2 variants via a human-cat-mouse-human circle,which could have important implications in establishing an effective strategy for combating SARS-CoV-2 viral infections. | Youwei Xu Canrong Wu Xiaodan Cao Chunyin Gu Heng Liu Meriting Jiang Xiaoxi Wang Qingning Yuan Kai Wu Jia Liu Deyi Wang Xianqing He Xueping Wang Su-Jun Deng H.Eric Xu Wanchao Yin | 2022 | Cell Research2022，32，7： | 6 |
| 3 | A complex structure of arrestin-2 bound to a G protein-coupled receptor显示文摘Arrestins comprise a family of signal regulators of G-protein-coupled receptors(GPCRs),which include arrestins 1 to 4.While arrestins 1 and 4 are visual arrestins dedicated to rhodopsin,arrestins 2 and 3(Arr2 and Arr3)areβ-arrestins known to regulate many nonvisual GPCRs.The dynamic and promiscuous coupling of Arr2 to nonvisual GPCRs has posed technical challenges to tackle the basis of arrestin binding to GPCRs.Here we report the structure of Arr2 in complex with neurotensin receptor 1(NTSR1),which reveals an overall assembly that is strikingly different from the visual arrestin–rhodopsin complex by a 90°rotation of Arr2 relative to the receptor.In this new configuration,intracellular loop 3(ICL3)and transmembrane helix 6(TM6)of the receptor are oriented toward the N-terminal domain of the arrestin,making it possible for GPCRs that lack the C-terminal tail to couple Arr2 through their ICL3.Molecular dynamics simulation and crosslinking data further support the assembly of the Arr2‒NTSR1 complex.Sequence analysis and homology modeling suggest that the Arr2‒NTSR1 complex structure may provide an alternative template for modeling arrestin–GPCR interactions. | Wanchao Yin Zhihai Li Mingliang Jin Yu-Ling Yin Parker Wde Waal Kuntal Pal Yanting Yin Xiang Gao Yuanzheng He Jing Gao Xiaoxi Wang Yan Zhang Hu Zhou Karsten Melcher Yi Jiang Yao Cong X.Edward Zhou Xuekui Yu H.Eric Xu | 2019 | Cell Research2019，29，12： | 4 |
| 4 | Structural basis for recognition of anti-migraine drug lasmiditan by the serotonin receptor 5-HT1F-G protein complex显示文摘Dear Editor,The serotonin 5-HTt receptor subtypes,including 5-HT_(1A)/5-HT_(1B)/5-HT_(1D),5-HT_(1E),and 5-HT_(1F),are G protein-coupled receptors(GPCRs)that respond to the endogenous neurotransmitter serotonin and couple preferentially to the G_(i/o)family of G proteins. | Sijie Huang Peiyu Xu Yangxia Tan Chongzhao You Yumu Zhang Yi Jiang H.Eric Xu | 2021 | Cell Research2021，31，9： | 3 |
| 5 | Mechanism of dopamine binding and allosteric modulation of the human D1 dopamine receptor显示文摘Dear Editor,Dopamine acts as an essential neurotransmitter whose signaling is conducted through five G protein-coupled receptors(GPCRs),dopamine D1 to D5 receptors(DRD1–DRD5).1 The D1-like receptors,comprising DRD1 and DRD5,primarily couple to the Gs family of G proteins to activate adenylyl cyclase and induce cAMP production.DRD1 is the most abundantly expressed dopamine receptor in the CNS.1 It is the central receptor mediating excitatory dopamine signaling in multiple dopaminergic pathways.Dysregulation of DRD1 signaling has been directly linked to Parkinson’s disease(PD),schizophrenia,and drug abuse. | Youwen Zhuang Brian Krumm Huibing Zhang X.Edward Zhou Yue Wang Xi-Ping Huang Yongfeng Liu Xi Cheng Yi Jiang Hualiang Jiang Cheng Zhang Wei Yi Bryan L.Roth Yan Zhang H.Eric Xu | 2021 | Cell Research2021，31，5： | 2 |
| 6 | Crystallographic Identification and Functional Characterization of Phospholipids as Ligands for the Orphan Nuclear Receptor Steroidogenic Factor-1显示文摘 | Yong Li Mihwa Choi Greg Cavey Jennifer Daugherty Kelly Suino Amanda Kovach Nathan C. Bingham Steven A. Kliewer H.Eric Xu | 2005 | Molecular Cell2005，，4： | 1 |
| 7 | Molecular basis of ligand recognition and activation of human V2 vasopressin receptor显示文摘Dear Editor,Vasopressin type 2 receptor(V2R)belongs to the vasopressin(VP)/oxytocin(OT)receptor subfamily of G protein-coupled receptors(GPCRs),which comprises at least four closely related receptor subtypes:V1aR,V1bR,V2R,and OTR. | Fulai Zhou Chenyu Ye Xiaomin Ma Wanchao Yin Tristan I.Croll Qingtong Zhou Xinheng He Xiaokang Zhang Dehua Yang Peiyi Wang H.Eric Xu Ming-Wei Wang Yi Jiang | 2021 | Cell Research2021，31，8： | 1 |
| 8 | Structure-based design of a hyperthermostable AgUricase for hyperuricemia and gout therapy显示文摘Arthrobacter globiformis Uricase(AgUricase)is a homotetrameric uricase with the potential for therapeutic use in treating hyperuricemia-related diseases.To achieve sufficient therapeutic effects,it is essential for this enzyme to have high thermostability and long half-life in physiological condition.To improve the thermostability of this enzyme,w e introduced a series of cysteine pair mutations into the AgUricase subunits based on its structural model and studied the thermostability of the mutant enzymes with introduced disulfide bridges.Two intersubunit cysteine pair mutations,K12C-E286C and S296C-S296C,were found to markedly increase the melting temperatures of the corresponding mutant enzymes compared with WTAgUricase.The crystal structure of the K12C-E286C mutant at 1.99 A resolution confirmed the formation of a distinct disulfide bond between the two subunits in the dimer.Structural analysis and biochemical data revealed that the C-terminal loop of AgUricase was flexible,and its interaction with neighboring subunits was required for the stability of the enzyme.We introduced an additional intersubunit K244C-C302 disulfide bond based on the crystal structure of the K12C-E286C mutant and confirmed that this additional disulfide bond further stabilized the flexible C-terminal loop and improved the thermostability of the enzyme.Disulfide cross-linking also protected AgUricase from protease digestion.Our studies suggest that the introduction of disulfide bonds into proteins is a potential strategy for enhancing the thermostability of multimeric proteins for medical applications. | Yi Shi Ting Wang X.Edward Zhou Qiu-feng Liu Yi Jiang H.Eric Xu | 2019 | Acta Pharmacologica Sinica2019，40，10： | 1 |
| 9 | Crystal Structure of the Glucocorticoid Receptor Ligand Binding Domain Reveals a Novel Mode of Receptor Dimerization and Coactivator Recognition显示文摘 | Randy K. Bledsoe Valerie G. Montana Thomas B. Stanley Chris J. Delves Christopher J. Apolito David D. McKee Thomas G. Consler Derek J. Parks Eugene L. Stewart Timothy M. Willson Millard H. Lambert John T. Moore Kenneth H. Pearce H.Eric Xu | 2002 | Cell2002，，1： | 1 |
| 10 | Structural insights into ligand binding and activation of the human thyrotropin-releasing hormone receptor显示文摘Dear Editor,The thyrotropin-releasing hormone(TRH)is the initlal hormone of the hypothalamo-pituitary-thyroid axis(HPT),a signaling cascade required for metabolic homeostasis and development in vertebrates.TRH is a tripeptide hormone(pGlu-His-Pro-NH2)that is synthesized in the hypothalamus and activates thyrotropin-releasing hormone receptor(TRHR),a member of class A G protein-coupled receptor(GPCR). | Youwei Xu Hongmin Cai Chongzhao You Xinheng He Qingning Yuan Hualiang Jiang Xi Cheng Yi Jiang H.Eric Xu | 2022 | Cell Research2022，32，9： | 0 |
| 11 | AlphaFold2 versus experimental structures: evaluation on G protein-coupled receptors显示文摘As important drug targets, G protein-coupled receptors (GPCRs) play pivotal roles in a wide range of physiological processes. Extensive efforts of structural biology have been made on the study of GPCRs. However, a large portion of GPCR structures remain unsolved due to structural instability. Recently, AlphaFold2 has been developed to predict structure models of many functionally important proteins including all members of the GPCR family. Herein we evaluated the accuracy of GPCR structure models predicted by AlphaFold2. We revealed that AlphaFold2 could capture the overall backbone features of the receptors. However, the predicted models and experimental structures were different in many aspects including the assembly of the extracellular and transmembrane domains, the shape of the ligand-binding pockets, and the conformation of the transducer-binding interfaces. These differences impeded the use of predicted structure models in the functional study and structure-based drug design of GPCRs, which required reliable high-resolution structural information. | Xin-heng He Chong-zhao You Hua-liang Jiang Yi Jjang H.Eric Xu Xi Cheng | 2023 | Acta Pharmacologica Sinica2023，44，1： | 0 |
| 12 | Structure basis for inhibition of SARS-CoV-2 by the feline drug GC376显示文摘Dear Editor,The coronavirus pandemic has brought public health challenges worldwide.The main protease(M^(pro)),also called 3CL^(pro)(3C-like protease),is encoded by the gene of non-structural protein 5(nsp5).It is an attractive antiviral drug target to halt the progress of severe acute respiratory syndrome coronavirus-2(SARS-COV-2),the causative pathogen of coronavirus disease 2019(COVID-19)[1].After viral infection in host cells,the replicase gene encodes two polyproteins,pp1a(486 kDa)and pp1ab(790 kDa). | Xiao-dong Luan Bin-xian Chen Wei-juan Shang Wan-chao Yin Ye Jin Lei-ke Zhang H.Eric Xu Shu-yang Zhang | 2023 | Acta Pharmacologica Sinica2023，44，1： | 0 |
| 13 | Molecular recognition of itch-associated neuropeptides by bombesin receptors显示文摘Dear Editor,Itch,especially persistent itch(or chronic pruritus)in patients with allergic skin diseases and/or neuropathic problems,significantly affects sleep,mood and individual health.Extensive efforts have been made to develop novel therapeutic strategies to fight itch.Unfortunately,there is no FDA-approved treatment for chronic pruritus despite great efforts in antipruritic research in the past few decades. | Changyao Li Youwei Xu Heng Liu Hongmin Cai Yi Jiang H.Eric Xu Wanchao Yin | 2023 | Cell Research2023，33，2： | 0 |
| 14 | GABAB receptor pas de deux:insights from high-resolution structures显示文摘The GABAb receptors are heterodimeric class C G proteincoupled receptors(GPCRs)that mediate the inhibitory neurotransmission in the central nervous system and they are drug targets for alcoholism and pain control.In a recent paper published in Cell Research,Mao et al.reported the first full-length GABAb heterodimer structures in both inactive and active states,providing a framework for understanding the activation of class C GPCRs and a template for designing allosteric modulators targeting the dimeric interface of the GABAb receptors. | Yi Jiang H.Eric Xu | 2020 | Cell Research2020，30，8： | 0 |
| 15 | Structure genomics of SARS-CoV-2 and its Omicron variant:drug design templates for COVID-19显示文摘Coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has brought an unprecedented public health crisis and persistently threatens to humanity.With tireless efforts from scientists around the world,understanding of the biology of coronavirus has been greatly enhanced over the past 2 years.Structural biology has demonstrated its powerful impact on uncovering structures and functions for the vast majority of SARS-CoV-2 proteins and guided the development of drugs and vaccines against COVID-19.In this review,we summarize current progress in the structural biology of SARS-CoV-2 and discuss important biological issues that remain to be addressed.We present the examples of structure-based design of Pfizer’s novel anti-SARS-CoV-2 drug PF-07321332(Paxlovid),Merck’s nucleotide inhibitor molnupiravir(Lagevrio),and VV116,an oral drug candidate for COVID-19.These examples highlight the importance of structure in drug discovery to combat COVID-19.We also discussed the recent variants of Omicron and its implication in immunity escape from existing vaccines and antibody therapies. | Can-rong Wu Wan-chao Yin Yi Jiang H.Eric Xu | 2022 | Acta Pharmacologica Sinica2022，43，12： | 0 |
| 16 | ARID3a from the ARID family: structure, role in autoimmune diseases and drug discovery显示文摘The AT-rich interaction domain (ARID) family of DNA-binding proteins is a group of transcription factors and chromatin regulators with a highly conserved ARID domain that recognizes specific AT-rich DNA sequences. Dysfunction of ARID family members has been implicated in various human diseases including cancers and intellectual disability. Among them, ARID3a has gained increasing attention due to its potential involvement in autoimmunity. In this article we provide an overview of the ARID family, focusing on the structure and biological functions of ARID3a. It explores the role of ARID3a in autoreactive B cells and its contribution to autoimmune diseases such as systemic lupus erythematosus and primary biliary cholangitis. Furthermore, we also discuss the potential for drug discovery targeting ARID3a and present a plan for future research in this field. | Cheng-cen Guo H.Eric Xu Xiong Ma | 2023 | Acta Pharmacologica Sinica2023，44，11： | 0 |
| 17 | Structural mechanism of calcium-mediated hormone recognition and Gβinteraction by the human melanocortin-1 receptor显示文摘Melanocortins are peptide hormones critical for the regulation of stress response,energy homeostasis,inflammation,and skin pigmentation.Their functions are mediated by five G protein-coupled receptors(MC1R–MC5R),predominately through the stimulatory G protein(Gs).MC1R,the founding member of melanocortin receptors,is mainly expressed in melanocytes and is involved in melanogenesis.Dysfunction of MC1R is associated with the development of melanoma and skin cancer.Here we present three cryo-electron microscopy structures of the MC1R–Gs complexes bound to endogenous hormoneα-MSH,a marketed drug afamelanotide,and a synthetic agonist SHU9119.These structures reveal the orthosteric binding pocket for the conserved HFRW motif among melanocortins and the crucial role of calcium ion in ligand binding.They also demonstrate the basis of differential activities among different ligands.In addition,unexpected interactions between MC1R and the Gβsubunit were discovered from these structures.Together,our results elucidate a conserved mechanism of calcium-mediated ligand recognition,a specific mode of G protein coupling,and a universal activation pathway of melanocortin receptors. | Shanshan Ma Yan Chen Antao Dai Wanchao Yin Jia Guo Dehua Yang Fulai Zhou Yi Jiang Ming-Wei Wang H.Eric Xu | 2021 | Cell Research2021，31，10： | 0 |
| 18 | Crystal structure of heliorhodopsin 48C12显示文摘Dear Editor,Heliorhodopsins(HeRs)are a new class of Microbial rhodopsins(MRs),with a low homology(<15%)to all other MRs and a unique membrane topology in which their N-termini face the intracellular side and C-termini face the extracellular side.1 To explore the photoactivation mechanism of HeRs,we sought to solve the structure of HeR 48C12(hereafter referred to as HeR).HeR protein was expressed in insect cells and purified by standard membrane purification methods(Supplementary information,Fig.S1a and Data S1).The purified HeR shows a monodispersed peak and exhibits a high thermostability(Tm=74°C,Supplementary information,Fig.S1b,c). | Yang Lu X.Edward Zhou Xiang Gao Na Wang Ruixue Xia Zhenmei Xu Yu Leng Yuying Shi Guangfu Wang Karsten Melcher H.Eric Xu Yuanzheng He | 2020 | Cell Research2020，30，1： | 0 |
| 19 | The cryo-electron microscopy structure of γ-secretase: towards complex assembly, substrate recognition and a catalytic mechanism显示文摘Alzheimer’s disease(AD)is the most common form of neurodegenerative disorder to cause dementia in the elderly.It afects millions of people worldwide and puts tremendous emotional and economic burden on afected families.It is estimated that care for AD patients costs more than$200 billion annually in the United States[1].Despite the | Yanyong Kang Karsten Melcher H.Eric Xu | 2015 | National Science Review2015，2，1： | 0 |
| 20 | Autoimmune diseases: targets, biology, and drug discovery显示文摘Autoimmune diseases (AIDs) arise from a breakdown in immunological self-tolerance, wherein the adaptive immune system mistakenly attacks healthy cells, tissues and organs. AIDs impose excessive treatment costs and currently rely on non-specific and universal immunosuppression, which only offer symptomatic relief without addressing the underlying causes. AIDs are driven by autoantigens, targeting the autoantigens holds great promise in transforming the treatment of these diseases. To achieve this goal, a comprehensive understanding of the pathogenic mechanisms underlying different AIDs and the identification of specific autoantigens are critical. In this review, we categorize AIDs based on their underlying causes and compile information on autoantigens implicated in each disease, providing a roadmap for the development of novel immunotherapy regimens. We will focus on type 1 diabetes (T1D), which is an autoimmune disease characterized by irreversible destruction of insulin-producing β cells in the Langerhans islets of the pancreas. We will discuss insulin as possible autoantigen of T1D and its role in T1D pathogenesis. Finally, we will review current treatments of TID and propose a potentially effective immunotherapy targeting autoantigens. | Shu-jie Li Yan-li Wu Juan-hua Chen Shi-yi Shen Jia Duan H.Eric Xu | 2024 | Acta Pharmacologica Sinica2024，45，4： | 0 |
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