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11.
Hong Wu Hong Zeng Aiping Dong Fengling Li Hao He Guillermo Senisterra Alma Seitova Shili Duan Peter J. Brown Masoud Vedadi Cheryl H. Arrowsmith Matthieu Schapira 《PloS one》2013,8(12)
Polycomb repressive complex 2 (PRC2) is an important regulator of cellular differentiation and cell type identity. Overexpression or activating mutations of EZH2, the catalytic component of the PRC2 complex, are linked to hyper-trimethylation of lysine 27 of histone H3 (H3K27me3) in many cancers. Potent EZH2 inhibitors that reduce levels of H3K27me3 kill mutant lymphoma cells and are efficacious in a mouse xenograft model of malignant rhabdoid tumors. Unlike most SET domain methyltransferases, EZH2 requires PRC2 components, SUZ12 and EED, for activity, but the mechanism by which catalysis is promoted in the PRC2 complex is unknown. We solved the 2.0 Å crystal structure of the EZH2 methyltransferase domain revealing that most of the canonical structural features of SET domain methyltransferase structures are conserved. The site of methyl transfer is in a catalytically competent state, and the structure clarifies the structural mechanism underlying oncogenic hyper-trimethylation of H3K27 in tumors harboring mutations at Y641 or A677. On the other hand, the I-SET and post-SET domains occupy atypical positions relative to the core SET domain resulting in incomplete formation of the cofactor binding site and occlusion of the substrate binding groove. A novel CXC domain N-terminal to the SET domain may contribute to the apparent inactive conformation. We propose that protein interactions within the PRC2 complex modulate the trajectory of the post-SET and I-SET domains of EZH2 in favor of a catalytically competent conformation. 相似文献
12.
随着全球建造业向数字化全面转型,建筑信息模型(BIM)的教学将是未来几年风景园林设计与实施的重要主题。介绍了风景园林专业BIM的教学方法和数字化竖向设计及其应用在BIM场地设计项目中的重要性。数字化竖向设计是实现BIM的途径。风景园林教育必须在其教学中讲解BIM建模方法和过程。 相似文献
13.
Dong A Xu X Edwards AM;Midwest Center for Structural Genomics;Structural Genomics Consortium Chang C Chruszcz M Cuff M Cymborowski M Di Leo R Egorova O Evdokimova E Filippova E Gu J Guthrie J Ignatchenko A Joachimiak A Klostermann N Kim Y Korniyenko Y Minor W Que Q Savchenko A Skarina T Tan K Yakunin A Yee A Yim V Zhang R Zheng H Akutsu M Arrowsmith C Avvakumov GV Bochkarev A Dahlgren LG Dhe-Paganon S Dimov S Dombrovski L Finerty P Flodin S Flores A Gräslund S Hammerström M Herman MD Hong BS 《Nature methods》2007,4(12):1019-1021
We tested the general applicability of in situ proteolysis to form protein crystals suitable for structure determination by adding a protease (chymotrypsin or trypsin) digestion step to crystallization trials of 55 bacterial and 14 human proteins that had proven recalcitrant to our best efforts at crystallization or structure determination. This is a work in progress; so far we determined structures of 9 bacterial proteins and the human aminoimidazole ribonucleotide synthetase (AIRS) domain. 相似文献
14.
H. W. Krause H.-J. Kreuzfeld U. Schmidt CH Dbler M. Michalik S. Taudien Ch. Fischer 《Chirality》1996,8(2):173-188
Substituted N-Cbz and N-Boc protected arylamino acrylic acids and esters have been prepared and used in asymmetric hydrogenations catalyzed by PROPRAPHOSRh. Stereoselectivities > 90% ee could be achieved, the rate of which is dependent on the position of the substituent in the aromatic ring. The N-Boc derivatives provide advantages compared with the N-Cbz analogues. The amino acid derivatives were fully characterized by 19F, 13C, and 1H NMR spectroscopy. © 1996 Wiley-Liss, Inc. 相似文献
15.
Amegbey G Chang Z Stothard P Yee A Arrowsmith C Wishart DS 《Journal of biomolecular NMR》2004,30(4):459-460
16.
Structural proteomics: a tool for genome annotation 总被引:1,自引:0,他引:1
Yakunin AF Yee AA Savchenko A Edwards AM Arrowsmith CH 《Current opinion in chemical biology》2004,8(1):42-48
In any newly sequenced genome, 30% to 50% of genes encode proteins with unknown molecular or cellular function. Fortunately, structural genomics is emerging as a powerful approach of functional annotation. Because of recent developments in high-throughput technologies, ongoing structural genomics projects are generating new structures at an unprecedented rate. In the past year, structural studies have identified many new structural motifs involved in enzymatic catalysis or in binding ligands or other macromolecules (DNA, RNA, protein). The efficiency by which function is deduced from structure can be further improved by the integration of structure with bioinformatics and other experimental approaches, such as screening for enzymatic activity or ligand binding. 相似文献
17.
Gutiérrez P Osborne MJ Siddiqui N Trempe JF Arrowsmith C Gehring K 《Protein science : a publication of the Protein Society》2004,13(3):659-667
aIF2 beta is the archaeal homolog of eIF2 beta, a member of the eIF2 heterotrimeric complex, implicated in the delivery of Met-tRNA(i)(Met) to the 40S ribosomal subunit. We have determined the solution structure of the intact beta-subunit of aIF2 from Methanobacterium thermoautotrophicum. aIF2 beta is composed of an unfolded N terminus, a mixed alpha/beta core domain and a C-terminal zinc finger. NMR data shows the two folded domains display restricted mobility with respect to each other. Analysis of the aIF2 gamma structure docked to tRNA allowed the identification of a putative binding site for the beta-subunit in the ternary translation complex. Based on structural similarity and biochemical data, a role for the different secondary structure elements is suggested. 相似文献
18.
Refolding out of guanidine hydrochloride is an effective approach for high-throughput structural studies of small proteins 下载免费PDF全文
Maxwell KL Bona D Liu C Arrowsmith CH Edwards AM 《Protein science : a publication of the Protein Society》2003,12(9):2073-2080
Low in vivo solubility of recombinant proteins expressed in Escherichia coli can seriously hinder the purification of structural samples for large-scale proteomic NMR and X-ray crystallography studies. Previous results from our laboratory have shown that up to one half of all bacterial and archaeal proteins are insoluble when overexpressed in E. coli. Although a number of strategies may be used to increase in vivo protein solubility, there are no generally applicable methods, and the expression of each insoluble recombinant protein must be individually optimized. For this reason, we have tested a generic denaturation/refolding protein purification procedure to assess the number of structural samples that could be generated by using this methodology. Our results show that a denaturation/refolding protocol is appropriate for many small proteins (相似文献
19.
Solution structure of ribosomal protein S28E from Methanobacterium thermoautotrophicum 总被引:2,自引:0,他引:2 下载免费PDF全文
Wu B Yee A Pineda-Lucena A Semesi A Ramelot TA Cort JR Jung JW Edwards A Lee W Kennedy M Arrowsmith CH 《Protein science : a publication of the Protein Society》2003,12(12):2831-2837
The ribosomal protein S28E from the archaeon Methanobacterium thermoautotrophicum is a component of the 30S ribosomal subunit. Sequence homologs of S28E are found only in archaea and eukaryotes. Here we report the three-dimensional solution structure of S28E by NMR spectroscopy. S28E contains a globular region and a long C-terminal tail protruding from the core. The globular region consists of four antiparallel beta-strands that are arranged in a Greek-key topology. Unique features of S28E include an extended loop L2-3 that folds back onto the protein and a 12-residue charged C-terminal tail with no regular secondary structure and greater flexibility relative to the rest of the protein. The structural and surface resemblance to OB-fold family of proteins and the presence of highly conserved basic residues suggest that S28E may bind to RNA. A broad positively charged surface extending over one side of the beta-barrel and into the flexible C terminus may present a putative binding site for RNA. 相似文献
20.
Yang Z Savchenko A Yakunin A Zhang R Edwards A Arrowsmith C Tong L 《The Journal of biological chemistry》2003,278(10):8804-8808
The open reading frame TM1643 of Thermotoga maritima belongs to a large family of proteins, with homologues in bacteria, archaea, and eukaryotes. TM1643 is found in an operon with two other genes that encode enzymes involved in the biosynthesis of NAD. In several bacteria, the gene in the position occupied by TM1643 encodes an aspartate oxidase (NadB), which synthesizes iminoaspartate as a substrate for NadA, the next enzyme in the pathway. The amino acid sequence of TM1643 does not share any recognizable homology with aspartate oxidase or with other proteins of known functions or structures. To help define the biological functions of TM1643, we determined its crystal structure at 2.6A resolution and performed a series of screens for enzymatic function. The structure reveals the presence of an N-terminal Rossmann fold domain with a bound NAD(+) cofactor and a C-terminal alpha+beta domain. The structural information suggests that TM1643 may be a dehydrogenase and the active site of the enzyme is located at the interface between the two domains. The enzymatic characterization of TM1643 revealed that it possesses NAD or NADP-dependent dehydrogenase activity toward l-aspartate but no aspartate oxidase activity. The product of the aspartate dehydrogenase activity is also iminoaspartate. Therefore, our studies demonstrate that two different enzymes, an oxidase and a dehydrogenase, may have evolved to catalyze the first step of NAD biosynthesis in prokaryotes. TM1643 establishes a new class of amino acid dehydrogenases. 相似文献