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1.
N-Methylpyrrolidone is a solvent molecule which has been shown to compete with acetyl-lysine-containing peptides for binding to bromodomains. From crystallographic studies, it has also been shown to closely mimic the acetamide binding motif in several bromodomains, but has not yet been directly pursued as a fragment in bromodomain inhibition. In this paper, we report the elaboration of N-methylpyrrolidone as a potential lead in fragment-based drug design. Firstly, N-methylpyrrolidone was functionalised to provide points for chemical elaboration. Then, the moiety was incorporated into analogues of the reported bromodomain inhibitor, Olinone. X-ray crystallography revealed that the modified analogues showed comparable binding affinity and structural mimicry to Olinone in the bromodomain binding site.  相似文献   
2.
陕南寒武系底部宽川铺组不仅保存了大量的小壳化石,还以磷酸盐化的方式立体保存了多种软躯体动物的胚胎和成体化石,为研究早期动物矿化模式、个体发育方式以及动物躯体构型的早期辐射过程提供了非常关键的信息。然而宽川铺生物群的研究大多聚焦于化石系统分类及亲缘关系探索,对生物群的沉积背景、埋藏过程和保存模式的分析甚少。本文以宽川铺生物群的核心产出层位——陕西省西乡县大河镇宽川铺组下部磷质碎屑灰岩为研究对象,对其中的一类管状化石圆管螺及其围岩进行了显微结构学和显微谱学综合分析,获得了化石显微结构和关键结构对应的元素、矿物成分等信息,讨论了管状化石圆管螺的埋藏过程和保存模式,并在此基础上对其生物学特征进行了初步探讨。该研究对理解宽川铺生物群的埋藏机制提供了新的线索。  相似文献   
3.
Rho GTPases are molecular switches that modulate a variety of cellular processes, most notably those involving actin dynamics. We have previously shown that yeast vacuolar membrane fusion requires re-organization of actin filaments mediated by two Rho GTPases, Rho1p and Cdc42p. Cdc42p initiates actin polymerization to facilitate membrane tethering; Rho1p has a role in the late stages of vacuolar fusion, but its mode of action is unknown. Here, we identified eEF1A as a vacuolar Rho1p-interacting protein. eEF1A (encoded by the TEF1 and TEF2 genes in yeast) is an aminoacyl-tRNA transferase needed during protein translation. eEF1A also has a second function that is independent of translation; it binds and organizes actin filaments into ordered cable structures. Here, we report that eEF1A interacts with Rho1p via a C-terminal subdomain. This interaction occurs predominantly when both proteins are in the GDP-bound state. Therefore, eEF1A is an atypical downstream effector of Rho1p. eEF1A does not promote vacuolar fusion; however, overexpression of the Rho1p-interacting subdomain affects vacuolar morphology. Vacuoles were destabilized and prone to leakage when treated with the eEF1A inhibitor narciclasine. We propose a model whereby eEF1A binds to Rho1p-GDP on the vacuolar membrane; it is released upon Rho1p activation and then bundles actin filaments to stabilize fused vacuoles. Therefore, the Rho1p-eEF1A complex acts to spatially localize a pool of eEF1A to vacuoles where it can readily organize F-actin.  相似文献   
4.
陕南早寒武世具口部的磷酸盐化Punctatus及其胚胎化石   总被引:3,自引:0,他引:3  
报道陕西南部灯影组宽川铺段地层中发现的Punctatus锥体标本、保留精美软组织特征的口部标本和可能的胚胎标本。对Punctatus软组织及整体形态功能研究表明,Punctatus在分类上可能更接近于腔肠动物的水螅型,代表初具原始触手的腔肠动物早期演化类型。在上万枚与Punctatus共生的球状化石中,发现若干枚可能的原肠期胚胎及胚胎发育晚期标本,在此基础上提出PunctatusemeiensisHe,1980花冠状口部可能经历的胚胎发育序列。  相似文献   
5.
Several different species and species groups of the familiy Favositidae from the Emsian and Middle Devonian limestones of the Tamworth Group (N.S.W., Australia) are described. The Emsian Sulcor Limestone Member yieldedFavosites sp. aff.F. basalticus (Goldfuss, 1826),Favosites sp. aff.F. salebrosus Etheridge, 1899,Favosites stellaris Chernyshev, 1937,Squameofavosites nitidus (Chapman, 1914),Sq. bryani (Jones, 1937),Pachyfavosites rariporosus Dubatolov, 1963, andP. tumulosus Yanet, 1965. The Middle Devonian Moore Creek Limestone Member yieldedFavosites ex gr.goldfussi D’Orbigny, 1850, exclusively. In the Emsian limestones occur favositids in a wide array of different facies, with most being found in stratified biostromes and in bedded nodular limestones. In the Middle Devonian most favositids are found in nodular and lumpy limestones which occur at the base and at the top of some successions   相似文献   
6.
Lipid droplets (LDs) are ubiquitous cellular organelles for lipid storage which are composed of a neutral lipid core bounded by a protein decorated phospholipid monolayer. Although lipid storage is their most obvious function, LDs are far from inert as they participate in maintaining lipid homeostasis through lipid synthesis, metabolism, and transportation. Furthermore, they are involved in cell signaling and other molecular events closely associated with human disease such as dyslipidemia, obesity, lipodystrophy, diabetes, fatty liver, atherosclerosis, and others. The last decade has seen a great increase in the attention paid to LD biology. Regardless, many fundamental features of LD biology remain obscure. In this review, we will discuss key aspects of LD biology including their biogenesis, growth and regression. We will also summarize the current knowledge about the role LDs play in human disease, especially from the perspective of the dynamics of the associated proteins. This article is part of a Special issue entitled Cardiac adaptations to obesity, diabetes and insulin resistance, edited by Professors Jan F.C. Glatz, Jason R.B. Dyck and Christine Des Rosiers.  相似文献   
7.
Two syndromes are known to be associated with WNT7A mutations: Al-Awadi–Raas-Rothschild syndrome (AARRS) and Fuhrmann syndrome. Woods et al. (2006) showed that there is complete and partial loss of WNT7A function in these two syndromes respectively. Therefore, both syndromes have similar clinical features but the phenotype in Fuhrmann syndrome is less severe. The G204S mutation was previously reported to result in AARRS phenotype in three Saudi families. In the current communication, we report on a different unrelated Saudi patient with the same mutation but the patient had Fuhrmann syndrome phenotype. We believe this case is important because it questions the presence of a phenotype–genotype correlation in WNT7A mutations and because it demonstrates that the G204S mutation may be associated with both AARRS and Fuhrmann phenotypes.  相似文献   
8.
Small molecules that correct protein misfolding and misprocessing defects offer a potential therapy for numerous human diseases. However, mechanisms underlying pharmacological correction of such defects, especially in heteromeric complexes with structurally diverse constituent proteins, are not well understood. Here we investigate how two chemically distinct compounds, glibenclamide and carbamazepine, correct biogenesis defects in ATP-sensitive potassium (KATP) channels composed of sulfonylurea receptor 1 (SUR1) and Kir6.2. We present evidence that despite structural differences, carbamazepine and glibenclamide compete for binding to KATP channels, and both drugs share a binding pocket in SUR1 to exert their effects. Moreover, both compounds engage Kir6.2, in particular the distal N terminus of Kir6.2, which is involved in normal channel biogenesis, for their chaperoning effects on SUR1 mutants. Conversely, both drugs can correct channel biogenesis defects caused by Kir6.2 mutations in a SUR1-dependent manner. Using an unnatural, photocross-linkable amino acid, azidophenylalanine, genetically encoded in Kir6.2, we demonstrate in living cells that both drugs promote interactions between the distal N terminus of Kir6.2 and SUR1. These findings reveal a converging pharmacological chaperoning mechanism wherein glibenclamide and carbamazepine stabilize the heteromeric subunit interface critical for channel biogenesis to overcome defective biogenesis caused by mutations in individual subunits.  相似文献   
9.
陕西镇巴早寒武世海绵骨针化石   总被引:1,自引:0,他引:1  
作者对采自陕西省镇巴县下寒武统西蒿坪段和水井沱组下部碳酸盐岩地层的海绵骨针化石进行了研究。三叶虫及小壳化石的生物地层学资料表明西蒿坪段和水井沱组下段属于筇竹寺阶。化石经室内醋酸浸泡处理后获得,骨针化石保存较好、类型多样,其中属于六射海绵纲的骨针3类,普通海绵纲的骨针6类,分类未定的骨针1类(Nabaviellasp.);并详细地对各类骨针化石进行了描述。虽然普通海绵骨针类型多样,但六射海绵的骨针丰度远高于普通海绵。简要地探讨了海绵骨针的保存方式,对比和分析了西蒿坪段和水井沱组海绵骨针化石组成的差异。结合同时代产自皖南荷塘组和云南澄江动物群中特异保存的海绵软躯体化石资料,认为虽然海绵动物起源于新元古代末期,但躯体海绵化石和骨针化石都显示海绵动物的大辐射事件发生在早寒武世筇竹寺期。  相似文献   
10.
早寒武世最早期梅树村期处于“寒武纪大爆发”序幕阶段。在这一时期,生物类群发生了大规模辐射演化及其身体构型的快速革新,形成与前寒武纪生物群明显不同的生物组合面貌。最近在陕南宽川铺地区早寒武世早期灯影组宽川铺段地层中发现了数十枚呈三维立体精美保存的磷酸盐化奇异星状生物化石标本,通过形态功能分析及与其共生的Punctatus的口盘类比表明,该奇异星状生物很可能属于腔肠动物Punctatus的口盘,星状体的中心为该生物的口部。而腔肠动物的出现标志着真后生动物的开始,在生物起源演化历程上占据着极其关键的位置。本文报道的奇异星状生物可能代表了初具原始触手的腔肠动物早期演化类型,为研究真后生动物起源演化、功能进化提供了新的实证材料。  相似文献   
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