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1.
Rasmussen SG DeVree BT Zou Y Kruse AC Chung KY Kobilka TS Thian FS Chae PS Pardon E Calinski D Mathiesen JM Shah ST Lyons JA Caffrey M Gellman SH Steyaert J Skiniotis G Weis WI Sunahara RK Kobilka BK 《Nature》2011,477(7366):549-555
G protein-coupled receptors (GPCRs) are responsible for the majority of cellular responses to hormones and neurotransmitters as well as the senses of sight, olfaction and taste. The paradigm of GPCR signalling is the activation of a heterotrimeric GTP binding protein (G protein) by an agonist-occupied receptor. The β(2) adrenergic receptor (β(2)AR) activation of Gs, the stimulatory G protein for adenylyl cyclase, has long been a model system for GPCR signalling. Here we present the crystal structure of the active state ternary complex composed of agonist-occupied monomeric β(2)AR and nucleotide-free Gs heterotrimer. The principal interactions between the β(2)AR and Gs involve the amino- and carboxy-terminal α-helices of Gs, with conformational changes propagating to the nucleotide-binding pocket. The largest conformational changes in the β(2)AR include a 14 ? outward movement at the cytoplasmic end of transmembrane segment 6 (TM6) and an α-helical extension of the cytoplasmic end of TM5. The most surprising observation is a major displacement of the α-helical domain of Gαs relative to the Ras-like GTPase domain. This crystal structure represents the first high-resolution view of transmembrane signalling by a GPCR. 相似文献
2.
Rasmussen SG Choi HJ Fung JJ Pardon E Casarosa P Chae PS Devree BT Rosenbaum DM Thian FS Kobilka TS Schnapp A Konetzki I Sunahara RK Gellman SH Pautsch A Steyaert J Weis WI Kobilka BK 《Nature》2011,469(7329):175-180
G protein coupled receptors (GPCRs) exhibit a spectrum of functional behaviours in response to natural and synthetic ligands. Recent crystal structures provide insights into inactive states of several GPCRs. Efforts to obtain an agonist-bound active-state GPCR structure have proven difficult due to the inherent instability of this state in the absence of a G protein. We generated a camelid antibody fragment (nanobody) to the human β(2) adrenergic receptor (β(2)AR) that exhibits G protein-like behaviour, and obtained an agonist-bound, active-state crystal structure of the receptor-nanobody complex. Comparison with the inactive β(2)AR structure reveals subtle changes in the binding pocket; however, these small changes are associated with an 11?? outward movement of the cytoplasmic end of transmembrane segment 6, and rearrangements of transmembrane segments 5 and 7 that are remarkably similar to those observed in opsin, an active form of rhodopsin. This structure provides insights into the process of agonist binding and activation. 相似文献
3.
AHN Yang-Keun PARK Young-Choong CHOI Kwang-Soon PARK Woo-Chool SEO Hae-Moon JUNG Kwang-Mo 《重庆邮电大学学报(自然科学版)》2009,21(2):222-227
Recently developed timeofflight principle based depthsensing video camera technologies provide precise perpixel range data in addition to color video. Such cameras will find application in robotics and visionbased human computer interaction scenarios such as games and gesture input systems. Timeofflight principle range cameras are becoming more and more available. They promise to make the 3D reconstruction of scenes easier, avoiding the practical issues resulting from 3D imaging techniques based on triangulation or disparity estimation. A spatial touch system was presented which uses a depthsensing camera to touch spatial objects and details on its implementation, and how this technology will enable new spatial interactions was speculated. 相似文献
4.
Yan-Ting Chen Yun Hu Qi-Yuan Yang Xiang-Dong Liu Jun Seok Son Jeanene M.de Avila Mei-Jun Zhu Min Du 《科学通报(英文版)》2021,(5):478-489
Maternal stress during pregnancy is prevailing worldwide,which exposes fetuses to intrauterine hyper glucocorticoids (GC),programming offspring to obesity and m... 相似文献
5.
Zusammenfassung Es wird angenommen, dass mindestens zwei Fraktionen von intrazellulärem Kalzium am Kupplungsprozess zwischen Reizung und Kontraktion des Herzens beteiligt sind.
This work was supported by grants from the Manitoba Heart Foundation and the Medical Research Council of Canada. We thank Mr.Stan Vivian for development of the PDP8/I computer program to analyze the calcium uptake curves. 相似文献
This work was supported by grants from the Manitoba Heart Foundation and the Medical Research Council of Canada. We thank Mr.Stan Vivian for development of the PDP8/I computer program to analyze the calcium uptake curves. 相似文献
6.
Yeon-Suk Oh Hee-Young Kwon Soo-Jin Jeong Ki-Young Park Sun-Young Kim Hyo-Jung Lee Hyo-Jeong Lee Eun-Ok Lee Kwang Seok Ahn Sung-Hoon Kim 《科学通报(英文版)》2009,54(23):4387-4392
Sojucktang (SJT) has long been used for the treatment of endometrial diseases in Korea. However, the mechanisms responsible for the SJT-induced apoptosis in endometrial cancer cells remain unclear. In the present study, SJT was demonstrated to show cytotoxic effect and induce apoptotic cell death via mitochondrial regulation in KLE endometrial cancer cells. Linderae Radix, Glycyrrhizae Radix, Zedoariae Rhizoma, Trogopterorum Faeces and Agelicae Gigantis Radix were found to be the potent constituent herbs of SJT to significantly decrease the viability of KLE cells by a tetra zolium salt (XTT) assay. Apoptotic bodies were observed in SJT-treated KLE cells by 4′-6-diamidino-2-phenylindole (DAPI) and TdT-mediated-dUTP nick-end labeling (TUNEL) assay. SJT also increased sub-G1 DNA contents of the cell cycle undergoing apoptosis in a dose-dependent manner. Furthermore, it was observed that SJT activated caspase-3 and cleaved poly (ADP-ribose) polymerase (PARP), and decreased mitochondrial membrane potential in a dose-dependent manner. Taken together, this study shows that SJT exerts anti-tumor activity against KLE endometrial cancer cells via mitochondrial dependent apoptosis induction. 相似文献
7.
Heeyoung Seok Haejeong Lee Eun-Sook Jang Sung Wook Chi 《Cellular and molecular life sciences : CMLS》2018,75(5):797-814
RNA interference (RNAi) has been widely adopted to repress specific gene expression and is easily achieved by designing small interfering RNAs (siRNAs) with perfect sequence complementarity to the intended target mRNAs. Although siRNAs direct Argonaute (Ago), a core component of the RNA-induced silencing complex (RISC), to recognize and silence target mRNAs, they also inevitably function as microRNAs (miRNAs) and suppress hundreds of off-targets. Such miRNA-like off-target repression is potentially detrimental, resulting in unwanted toxicity and phenotypes. Despite early recognition of the severity of miRNA-like off-target repression, this effect has often been overlooked because of difficulties in recognizing and avoiding off-targets. However, recent advances in genome-wide methods and knowledge of Ago–miRNA target interactions have set the stage for properly evaluating and controlling miRNA-like off-target repression. Here, we describe the intrinsic problems of miRNA-like off-target effects caused by canonical and noncanonical interactions. We particularly focus on various genome-wide approaches and chemical modifications for the evaluation and prevention of off-target repression to facilitate the use of RNAi with secured specificity. 相似文献
8.
单晶样品Pr3Co和Nd3Co的磁化率测量 总被引:1,自引:1,他引:0
我们对金属间化合物 Pr3Co和 Nd3Co单晶样品的磁化率在磁场 H=14π× 1 0 7A/M,温度范围为77K~ 3 0 0 K的条件下进行了测量 ,并计算得出它们的有效玻耳磁子 相似文献
9.
Yagoda N von Rechenberg M Zaganjor E Bauer AJ Yang WS Fridman DJ Wolpaw AJ Smukste I Peltier JM Boniface JJ Smith R Lessnick SL Sahasrabudhe S Stockwell BR 《Nature》2007,447(7146):864-868
Therapeutics that discriminate between the genetic makeup of normal cells and tumour cells are valuable for treating and understanding cancer. Small molecules with oncogene-selective lethality may reveal novel functions of oncoproteins and enable the creation of more selective drugs. Here we describe the mechanism of action of the selective anti-tumour agent erastin, involving the RAS-RAF-MEK signalling pathway functioning in cell proliferation, differentiation and survival. Erastin exhibits greater lethality in human tumour cells harbouring mutations in the oncogenes HRAS, KRAS or BRAF. Using affinity purification and mass spectrometry, we discovered that erastin acts through mitochondrial voltage-dependent anion channels (VDACs)--a novel target for anti-cancer drugs. We show that erastin treatment of cells harbouring oncogenic RAS causes the appearance of oxidative species and subsequent death through an oxidative, non-apoptotic mechanism. RNA-interference-mediated knockdown of VDAC2 or VDAC3 caused resistance to erastin, implicating these two VDAC isoforms in the mechanism of action of erastin. Moreover, using purified mitochondria expressing a single VDAC isoform, we found that erastin alters the permeability of the outer mitochondrial membrane. Finally, using a radiolabelled analogue and a filter-binding assay, we show that erastin binds directly to VDAC2. These results demonstrate that ligands to VDAC proteins can induce non-apoptotic cell death selectively in some tumour cells harbouring activating mutations in the RAS-RAF-MEK pathway. 相似文献
10.
LEE Eun-Ok LEE Hyo-Jung LEE Hyo-Jeong KIM Kwan-Hyun WON Sook-Hyun LEE Jae-Dong AHN Kwang Seok AHN Kyoo Seok KIM Jung-Hyo YU Young-Beob KIM Sung-Hoon 《科学通报(英文版)》2009,54(2):227-233
Oriental herbal medicines have been widely used for the prevention or treatment of various diseases including cancer in Asia.
However, to prove their chemo preventive efficacies in modern times, scientific evidence for those herbal medicines is required.
Thus, in the present study, an effective herbal cocktail Bojungbangdocktang (BJBDT) was investigated to elucidate antiangiogenic
mechanism in vitro and in vivo. BJBDT significantly inhibited vascular endothelial growth factor (VEGF) induced proliferation in HUVECs at nontoxic concentrations,
despite weak cytotoxicity against human umbilical vein endothelial cells (HUVECs). BJBDT also significantly suppressed VEGF-induced
migration and tube formation of HUVECs. Furthermore, BJBDT treatment resulted in pale color and low hemoglobin level in Matrigel
plugs, as well as dark red color and high hemoglobin level in untreated control. Interestingly, BJBDT specifically inhibited
the binding of VEGF to vascular endothelial growth factor receptor 2 (VEGFR2), but not VEGFR1. In addition, friedelin, formononetin,
ginsenoside Rb1, naringin, atractyloside, diosgenin, and allantonin were identified from BJBDT by high-performance liquid
chromatography (HPLC) analysis as a quality of control. Taken together, these results suggest that BJBDT is a potent angiogenesis
inhibitor blocking the VEGF/VEGFR2 signaling pathway in HUVECs.
Supported by the Korea Science and Engineering Foundation Grant from the Korean Government (Ministry of Science and Technology)
(Grant No. R13-2007-019-00000-0) 相似文献