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| 1 | Androgen receptor: structure, role in prostate cancer and drug discovery显示文摘Androgens and androgen receptors (AR) play a pivotal role in expression of the male phenotype. Several diseases, such as androgen insensitivity syndrome (AIS) and prostate cancer, are associated with alterations in AR functions. Indeed, androgen blockade by drugs that prevent the production of androgens and/or block the action of the AR inhibits prostate cancer growth. However, resistance to these drugs often occurs after 2-3 years as the patients develop castration-resistant prostate cancer (CRPC). In CRPC, a functional AR remains a key regulator. Early studies focused on the functional domains of the AR and its crucial role in the pathology. The elucidation of the structures of the AR DNA binding domain (DBD) and ligand binding domain (LBD) provides a new framework for understanding the functions of this receptor and leads to the development of rational drug design for the treatment of prostate cancer. An overview of androgen receptor structure and activity, its actions in prostate cancer, and how structural information and high-throughput screening have been or can be used for drug discovery are provided herein. | MH Eileen TAN Jun LI H Eric XU Karsten MELCHER Eu-leong YONG | 2015 | Acta Pharmacologica Sinica2015，36，1： | 39 |
| 2 | Amyloid beta: structure, biology and structure-based therapeutic development显示文摘淀粉的贝它肽(A) 通过 transmembrane 蛋白质的解朊的处理被生产,淀粉的先锋蛋白质(应用软件) ,由 - 并且 -secretases。在大脑的累积被建议是在 Alzheimers 疾病的致病的一个早有毒的事件,它是在大脑与匾和混乱联系的痴呆的最普通的形式。当前, A 的生理、病理学的形式是什么,是不清楚的并且由由什么机制, A 引起痴呆。而且,没有有效的药停止或逆行 Alzheimers 的前进疾病。在这份报纸,我们考察 A 的结构,生物功能,和 neurotoxicity 角色。我们也讨论与 A 交往并且调停的潜在的受体吸入,清理,和新陈代谢。另外,我们为治疗 Alzheimers 疾病总结治疗学的开发和不同策略的最近的进展。最后,我们将在象为 Alzheimers 疾病的治疗答应策略选择一样寻找新奇、潜在地有效的代理人在进步上报导。这些前景包括对 A,它的受体和字形物蛋白质起作用的代理人,例如对 A 的小分子,疫苗和抗体;禁止者或调节的人 - 并且 -secretase;降级 A 的朊酶;字形物蛋白质禁止者和疫苗;淀粉的染料和 microRNAs。 | Guo-fang CHEN Ting-hai XU Yan YAN Yu-ren ZHOU Yi JIANG Karsten MELCHER H Eric XU | 2017 | Acta Pharmacologica Sinica2017，38，9： | 39 |
| 3 | An ABA-mimicking ligand that reduces water loss and promotes drought resistance in plants显示文摘Abscisic 酸(骆驼毛的织物) 是最重要的荷尔蒙让植物抵抗干旱和另外的不能生活的压力。骆驼毛的织物直接绑在骆驼毛的织物受体的 PYR/PYL 家庭,导致类型 2C 磷酸酶(PP2C ) 和下游的骆驼毛的织物发信号的激活的抑制。骆驼毛的织物由小分子发信号的干预能帮助植物克服象干旱,寒冷和土壤咸度那样的不能生活的压力,这被想象。然而,由植物酶的化学不稳定性和快速的分解代谢限制骆驼毛的织物本身的实际申请。这里,我们报导一件小分子骆驼毛的织物的鉴定模仿(AM1 ) 那充当骆驼毛的织物受体的家庭的多重成员的有势力使活跃之物。在 Arabidopsis, AM1 激活高度类似于由骆驼毛的织物导致了那的一个基因网络。有 AM1 的处理禁止种子萌芽,阻止叶水损失,并且支持干旱抵抗。我们与 PYL2 骆驼毛的织物受体和 HAB1 PP2C 在建筑群解决了 AM1 的水晶结构,它表明 AM1 调停交往的 gate-latch-lock 网络,在骆驼毛的织物界限 receptor/PP2C 建筑群被保存的一个结构的特征。一起,这些结果证明一件单个小分子骆驼毛的织物模仿能激活多重骆驼毛的织物受体并且保护植物免受水损失和干旱应力的伤害。而且, AM1 复杂水晶结构为设计 ABA-mimicking 小分子的下一代提供一个结构的基础。 | Minjie Cao Xue Liu Yan Zhang Xiaoqian Xue X EdwardZhou Karsten Melcher Pan Gao Fuxing Wang Liang Zeng Yang Zhao Pan Deng Dafang Zhong Jian-Kang Zhu H Eric Xu Yong Xu | 2013 | Cell Research2013，23，8： | 17 |
| 4 | Structural basis of AMPK regulation by adenine nucleotides and glycogen显示文摘激活安培的蛋白质 kinase (AMPK ) 为糖尿病,肥胖,和癌症的治疗是一个中央细胞的精力传感器和精力动态平衡,和一个有希望的药目标的管理者。这里我们人的 α 的现在的低分辨率的水晶结构; 1 β 2 γ 1 holo-AMPK 建筑群跳了到它的 allosteric 调节的人安培和肝糖模仿 cyclodextrin,两个在 phosphorylated (4.05 Å) 并且 non-phosphorylated (4.60 Å) 状态。另外,我们解决了 2.95 Å人的 kinase 领域(KD ) 的结构跳了到邻近的 autoinhibitory 领域(帮助) 并且表现了广泛生物化学并且 mutational 研究。一起,这些研究由安培和肝糖说明 allosteric AMPK 调整的内在的机制,其绑定改变在交替的帮助(安培) 和糖类绑定模块(肝糖) 之间的 equilibria 相互作用。 | Xiaodan Li Lili Wang X Edward Zhou Jiyuan Ke Parker W de Waal Xin Gu M H Eileen Tan Dongye Wang Donghai Wu H Eric Xu Karsten Melcher | 2015 | Cell Research2015，25，1： | 8 |
| 5 | Destabilization of strigolactone receptor DWARF14 by binding of ligand and E3-1igase signaling effector DWARF3显示文摘 | Li-Hua Zhao X Edward Zhou Wei Yi Zhongshan Wu Yue Liu Yanyong Kang Li Hou Parker W de Waal Suling Li Yi Jiang Adrian Scaffidi Gavin R Flematti Steven M Smith Vinh Q Lam Patrick R Griffin YonghongWang Jiayang Li Karsten Melcher H Eric Xu | 2015 | Cell Research2015，25，11： | 7 |
| 6 | Kirigami-inspired,highly stretchable microsupercapacitor patches fabricated by laser conversion and cutting显示文摘The recent developments in material sciences and rational structural designs have advanced the field of compliant and deformable electronics systems.However,many of these systems are limited in either overall stretchability or areal coverage of functional components.Here,we design a construct inspired by Kirigami for highly deformable microsupercapacitor patches with high areal coverages of electrode and electrolyte materials.These patches can be fabricated in simple and efficient steps by laser-assisted graphitic conversion and cutting.Because the Kirigami cuts significantly increase structural compliance,segments in the patches can buckle,rotate,bend and twist to accommodate large overall deformations with only a small strain(<3%)in active electrode areas.Electrochemical testing results have proved that electrical and electrochemical performances are preserved under large deformation,with less than 2%change in capacitance when the patch is elongated to 382.5%of its initial length.The high design flexibility can enable various types of electrical connections among an array of supercapacitors residing in one patch,by using different Kirigami designs. | Renxiao Xu Anton Zverev Aaron Hung Caiwei Shen Lauren Irie Geoffrey Ding Michael Whitmeyer Liangjie Ren Brandon Griffin Jack Melcher Lily Zheng Xining Zang Mohan Sanghadasa Liwei Lin | 2018 | Microsystems & Nanoengineering2018，4，1： | 6 |
| 7 | Structure and mechanism for recognition of peptide hormones by Class B G-protein-coupled receptors显示文摘班 B G-protein-coupled 受体(GPCR ) 是为包括 glucagon,甲状旁腺的荷尔蒙,和 calcitonin 的肽荷尔蒙的受体。这些受体涉及大量生理的活动,从到骨胳的系统的开发和维护的新陈代谢的规定和压力控制。因此,他们是重要的药目标因为糖尿病,骨质疏松症,和应力的处理联系了混乱。班 B GPCR 被组织成二个模块化的领域:一个细胞外的领域(ECD ) 和包含七 transmembrane helices (TM 领域) 的螺旋状的捆。ECD 为荷尔蒙绑定的高亲密关系和特性负责,并且 TM 域为联合到下游的 G 蛋白质的受体激活和信号被要求。尽管全身的受体的结构仍然保持未知, ECD 结构是为很多班 B GPCR 描绘的井,揭示为 ligand 识别的普通褶层。这评论总结为治疗学的目的在肽荷尔蒙类似物的设计由班 B ECD 和他们的含意指导荷尔蒙绑定的一般结构的原则。 | Kuntal PAL Karsten MELCHER H Eric XU | 2012 | Acta Pharmacologica Sinica2012，33，3： | 5 |
| 8 | Adhesion of PBO Fiber in Epoxy Composites显示文摘The high mechanical and thermal performance of poly p-phenylene-2, 6-benzobisoxazole(PBO) fiber provides great potential applications as reinforcement fibers for composites. A composite of PBO fiber and epoxy resin has excellent electrical insulation properties, therefore, it is considered to be the best choice for the reinforcement in high magnetic field coils for pulsed magnetic fields up to 100 T. However, poor adhesion between PBO fiber and matrix is found because of the chemically inactive and/or relatively smooth surface of the reinforcement fiber preventing efficient chemical bonding in the interface, which is a challenging issue to improve mechanical properties. Here, we report the surface modification of PBO fibers by ultraviolet (UV) irradiation, O2 and NH3 plasma, as well as acidic treatments. The interfacial adhesion strength values of all the treatments show the similar level as determined for aramid fibers by pull-out tests, a significant impact on fiber-matrix-adhesion was not achieved. The surface free energy and roughness are increased for both sized and extracted fibers after plasma treatments together with maleic anhydride grafting. The sized fiber shows marginal improvement in adhesion strength and no change in fiber tensile strength because of the barrier effect of the finish. For the extracted fiber, different surface treatments either show no apparent effect or cause reduction in adhesion strength. Atomic force microscopy (AFM) topography analysis of the fracture surfaces proved adhesive failure at the fiber surface. The fiber surface roughness is increased and more surface flaws are induced, which could result in coarse interface structures when the treated fiber surface has no adequate wetting and functional groups. The adhesion failure is further confirmed by similar adhesion strength and compression shear strength values when the fiber was embedded in various epoxy resins with different temperature behavior. The tensile strength of fiber is sensitive to surface treatment conditions as revealed by a bimodal Weibull statistical distribution analysis. Considerable strength reduction occurred, particularly for cases of acidic and plasma treatments, while UV irradiation shows the better ability to retain fiber strength. | MADER Edith MELCHER Steffen 刘建文 高尚林 | 2007 | Journal of Donghua University(English Edition)2007，24，2： | 4 |
| 9 | 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 |
| 10 | Abscisic acid perception and signaling: structura mechanisms and applications显示文摘不利环境条件是对农业产量的威胁因此在生计,健康和经济上施加全球效果。Abscisic 酸(骆驼毛的织物) 是调整不能生活的压力忍耐的重要植物荷尔蒙,从而允许种应付环境压力。以前,试图开发发信号的内在的骆驼毛的织物被困难在真正的骆驼毛的织物受体的鉴定妨碍了的机制的完全的理解。骆驼毛的织物受体的 PYR/PYL/RCAR 家庭的发现因此在克服这些障碍的努力代表了一个主要里程碑;从那以后,许多结构、功能的研究提供了详细卓见进从骆驼毛的织物感觉到骆驼毛的织物应答的基因抄写的激活的过程。这理解骆驼毛的织物感觉的机制并且发信号在压力抵抗的庄稼的遗传工程以及在新合成骆驼毛的织物收缩筋的设计用作最近的、初步的开发的基础,它为应力公差的农业改进保持大诺言。 | Ley Moy NG Karsten MELCHER Bin Tean TEH H Eric XU | 2014 | Acta Pharmacologica Sinica2014，35，5： | 4 |
| 11 | Structure and activation of rhodopsin显示文摘视紫红质是第一 G-protein-coupled 受体(GPCR ) ,它的三维的结构由 X 光检查晶体学解决了。视紫红质的水晶结构在视觉系统揭示了 photoreception 和信号 transduction 的分子的机制。尽管几另外的 GPCR 水晶结构在过去几年被报导了,视紫红质结构为理解另外的 GPCR 的结构、功能的特征仍然是一个重要模型。这评论总结结构的特征, photoactivation,和视紫红质的 G 蛋白质信号 transduction。 | X Edward ZHOU Karsten MELCHER H Eric XU | 2012 | Acta Pharmacologica Sinica2012，33，3： | 4 |
| 12 | The structural basis of the dominant negative phenotype of the Gαi1β1Y2 G203A/A326S heterotrimer显示文摘 | Ping LIU Ming-zhu JIA X Edward ZHOU Parker W DE WAAL Bradley M DICKSON Bo LlU Li HOU Yan-ting YIN Ya n-yong KANG Yi SHI Karsten MELCHER H Eric XU Yi JIANG | 2016 | Acta Pharmacologica Sinica2016，37，9： | 3 |
| 13 | Burden of onchocerciasis-associated epilepsy:first estimates and research priorities显示文摘Background:Since the 1990s,evidence has accumulated of an increased prevalence of epilepsy in onchocerciasisendemic areas in Africa as compared to onchocerciasis-free areas.Although the causal relationship between onchocerciasis and epilepsy has yet to be proven,there is likely an association.Here we discuss the need for disease burden estimates of onchocerciasis-associated epilepsy(OAE),provide them,detail how such estimates should be refined,and discuss the socioeconomic impact of OAE,including a cost-estimate for anti-epileptic drugs.Main body:Providing OAE burden estimates may aid prevention of epilepsy in onchocerciasis-endemic areas by inciting and informing collaboration between onchocerciasis control programmes and mental health services.Epilepsy not only massively impacts the health of those affected,but it also carries a high socioeconomic burden for the households and communities involved.We used previously published geospatial estimates of onchocerciasis in Africa and a separately published logistic regression model quantifying the association between onchocerciasis and epilepsy to estimate the number of OAE cases.We then applied disability weights for epilepsy to quantify the burden in terms of years of life lived with disability(YLD)and estimate the cost of treatment.We estimate that in 2015 roughly 117000 people were affected by OAE across onchocerciasis-endemic areas previously under the African Programme for Onchocerciases control(APOC)mandate where OAE has ever been reported or suspected,and another 264000 persons in onchocerciasis-endemic areas where OAE has never been investigated before.The total number of YLDs due to OAE was 39300 and 88700 in these areas respectively,based on a weighted mean disability weight of 0.336.The burden of OAE is approximately 13%of the total YLDs attributable to onchocerciasis and 10%of total YLDs attributable to epilepsy.We estimated that by 2015 the total costs of treatment with antiepileptic drug for OAE cases would have been a minimum of 12.4 million US$.Conclusions:These estimates suggest a considerable health,social and economic burden of OAE in Africa.The treatment and care for people with epilepsy,especially in hyperendemic onchocerciasis areas with high epilepsy prevalence thus requires more financial and human resources. | Natalie V.S.Vinkeles Melchers Sarah Mollenkopf Robert Colebunders Michael Edlinger Luc E.Coffeng Julia Irani Tresor Zola Joseph N.Siewe Sake Jde Vlas Andrea S.Winkler Wilma A.Stolk | 2018 | Infectious Diseases of Poverty2018，7，1： | 3 |
| 14 | Structural basis of the Norrin-Frizzled 4 interaction显示文摘 | Guobo Shen Jiyuan Ke Zhizhi Wang Zhihong Cheng Xin Gu Yuquan Wei Karsten Melcher H Eric Xu Wenqing Xu | 2015 | Cell Research2015，25，9： | 3 |
| 15 | Czochralski growth of rare earth oxyorthosilicate single crystals显示文摘 | MELCHER C L MANENTE R A PETERSON C A | 1993 | J Cryst Growth1993，128，： | 2 |
| 16 | Generation and characterization of a human nanobody against VEGFR-2显示文摘瞄准:Nanobody 是由一个单个 monomeric 变量抗体领域组成的抗体碎片,它能被用于许多 biotechnological 和治疗学的目的。这个工作的目的是从噬菌体显示器 library.Methods 对 VEGFR-2 domain3 (VEGFR D3 ) 孤立并且描绘人的信号域抗体:与与 VEGFR2 D3 的高亲密关系生产抗原特定的 recombinant nanobodies,液体阶段 panning 策略被用于 panning 的 all rounds。为 nanobody 表示和纯化,四 VEGFR2 堵住 D3 克隆是进 pETduet-biotin-MBP 表示向量的 subcloned。recombinant 蛋白质带了一个 MBP 标签由亲密关系层析便于纯化。Recombinant NTV (1-4 ) 在另外的胶化过滤层析步以后被获得。在 VEGFR2 D3 和 NTV (1-4 ) 之间的相互作用与基于光的 AlphaScreen 试金和 SPR 试金被估计。Anti-angiogenesis 效果在人的脐的静脉 endothelial 房间(HUVEC ) 被检验 .Results:在 AlphaScreen 试金, NTV1 (100 和 200 nmol/L ) 与 VEGFR2 D3 得到了最高有约束力的信号;NTV2 与 VEGFR2 D3 显示出中等相互作用;NTV3 和 NTV4 展出了有 VEGFR2 D3 的很少或没有相互作用。在 SPR 试金, NTV1 与一个平衡分离常数为 VEGFR2 D3 显示了一种高亲密关系(K 49 ± 的 D ) ; 1.8 nmol/L。NTV1 (1-1000 nmol/L ) dose-dependently 由 HUVECs.Conclusion 禁止了 HUVEC 和 endothelial 试管形成的增长:nanobody NTV1 是堵住 VEGFR2 的一个潜在的治疗学的候选人。这研究为指向 VEGFR2 的基于 nanobody 的癌症治疗学的开发提供新奇、有希望的策略。 | Lin MA Kai GU Cheng-hai ZHANG Xue-tao CHEN Yi JIANG Karsten MELCHER Juan ZHANG Min WANG H Eric XU | 2016 | Acta Pharmacologica Sinica2016，37，6： | 2 |
| 17 | Structure of the PRC2 complex and application to drug discovery显示文摘polycomb 压抑的建筑群 2 (PRC2 ) 建筑群催化 histone H3 离氨酸 27 的 tri-methylation (H3K27 ) ,与基因 silencing 联系的一个压抑的染色质标记。PRC2 的 Overexpression 和变化在许多癌症被发现,使 PRC2 的催化活动成为癌症治疗的一个重要目标。这评论加亮人的 PRC2 复杂界限的最近的结构的突破到 H3K27 肽和一个小分子禁止者,它提供极其需要的卓见进指向 PRC2 的药发现。 | Yi SHI Xiao-xi WANG You-wen ZHUANG Yi JIANG Karsten MELCHER H Eric XU | 2017 | Acta Pharmacologica Sinica2017，38，7： | 2 |
| 18 | Molecular assembly of rhodopsin with G protein-coupled receptor kinases显示文摘 | He, Yuanzheng Gao, Xiang Goswami, Devrishi Hou, Li Pal, Kuntal Yin, Yanting Zhao, Gongpu Ernst, Oliver P. Griffin, Patrick Melcher, Karsten Xu, H. Eric | 2017 | Cell Research2017，27，6： | 2 |
| 19 | The evolving role of dendritic cells in cancer therapy显示文摘 | EJ Ilett RJD Prestwich AA Melcher | 2010 | Expert Opinion on Biological Therapy2010，，3： | 2 |
| 20 | Importance sampling in structural systems显示文摘 | Melchers R E | 1989 | Structural Safety1989，6，： | 2 |
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