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排序方式: 共有252条查询结果,搜索用时 15 毫秒
41.
Structure of the mammalian 80S ribosome at 8.7 A resolution 总被引:1,自引:0,他引:1
Chandramouli P Topf M Ménétret JF Eswar N Cannone JJ Gutell RR Sali A Akey CW 《Structure (London, England : 1993)》2008,16(4):535-548
In this paper, we present a structure of the mammalian ribosome determined at approximately 8.7 A resolution by electron cryomicroscopy and single-particle methods. A model of the ribosome was created by docking homology models of subunit rRNAs and conserved proteins into the density map. We then modeled expansion segments in the subunit rRNAs and found unclaimed density for approximately 20 proteins. In general, many conserved proteins and novel proteins interact with expansion segments to form an integrated framework that may stabilize the mature ribosome. Our structure provides a snapshot of the mammalian ribosome at the beginning of translation and lends support to current models in which large movements of the small subunit and L1 stalk occur during tRNA translocation. Finally, details are presented for intersubunit bridges that are specific to the eukaryotic ribosome. We suggest that these bridges may help reset the conformation of the ribosome to prepare for the next cycle of chain elongation. 相似文献
42.
Libusha Kelly Ursula Pieper Narayanan Eswar Franklin A. Hays Min Li Zygy Roe-Zurz Deanna L. Kroetz Kathleen M. Giacomini Robert M. Stroud Andrej Sali 《Journal of structural and functional genomics》2009,10(4):269-280
Membrane proteins serve as cellular gatekeepers, regulators, and sensors. Prior studies have explored the functional breadth
and evolution of proteins and families of particular interest, such as the diversity of transport-associated membrane protein
families in prokaryotes and eukaryotes, the composition of integral membrane proteins, and family classification of all human
G-protein coupled receptors. However, a comprehensive analysis of the content and evolutionary associations between membrane
proteins and families in a diverse set of genomes is lacking. Here, a membrane protein annotation pipeline was developed to
define the integral membrane genome and associations between 21,379 proteins from 34 genomes; most, but not all of these proteins
belong to 598 defined families. The pipeline was used to provide target input for a structural genomics project that successfully
cloned, expressed, and purified 61 of our first 96 selected targets in yeast. Furthermore, the methodology was applied (1)
to explore the evolutionary history of the substrate-binding transmembrane domains of the human ABC transporter superfamily,
(2) to identify the multidrug resistance-associated membrane proteins in whole genomes, and (3) to identify putative new membrane
protein families. 相似文献
43.
Marnix H. Medema Peter Cimermancic Andrej Sali Eriko Takano Michael A. Fischbach 《PLoS computational biology》2014,10(12)
Bacterial secondary metabolites are widely used as antibiotics, anticancer drugs, insecticides and food additives. Attempts to engineer their biosynthetic gene clusters (BGCs) to produce unnatural metabolites with improved properties are often frustrated by the unpredictability and complexity of the enzymes that synthesize these molecules, suggesting that genetic changes within BGCs are limited by specific constraints. Here, by performing a systematic computational analysis of BGC evolution, we derive evidence for three findings that shed light on the ways in which, despite these constraints, nature successfully invents new molecules: 1) BGCs for complex molecules often evolve through the successive merger of smaller sub-clusters, which function as independent evolutionary entities. 2) An important subset of polyketide synthases and nonribosomal peptide synthetases evolve by concerted evolution, which generates sets of sequence-homogenized domains that may hold promise for engineering efforts since they exhibit a high degree of functional interoperability, 3) Individual BGC families evolve in distinct ways, suggesting that design strategies should take into account family-specific functional constraints. These findings suggest novel strategies for using synthetic biology to rationally engineer biosynthetic pathways. 相似文献
44.
Flavio De Maio Giuseppe Maulucci Mariachiara Minerva Saber Anoosheh Ivana Palucci Raffaella Iantomasi Valentina Palmieri Serena Camassa Michela Sali Maurizio Sanguinetti Wilbert Bitter Riccardo Manganelli Marco De Spirito Giovanni Delogu 《PloS one》2014,9(11)
PE_PGRS proteins are unique to the Mycobacterium tuberculosis complex and a number of other pathogenic mycobacteria. PE_PGRS30, which is required for the full virulence of M. tuberculosis (Mtb), has three main domains, i.e. an N-terminal PE domain, repetitive PGRS domain and the unique C-terminal domain. To investigate the role of these domains, we expressed a GFP-tagged PE_PGRS30 protein and a series of its functional deletion mutants in different mycobacterial species (Mtb, Mycobacterium bovis BCG and Mycobacterium smegmatis) and analysed protein localization by confocal microscopy. We show that PE_PGRS30 localizes at the mycobacterial cell poles in Mtb and M. bovis BCG but not in M. smegmatis and that the PGRS domain of the protein strongly contributes to protein cellular localization in Mtb. Immunofluorescence studies further showed that the unique C-terminal domain of PE_PGRS30 is not available on the surface, except when the PGRS domain is missing. Immunoblot demonstrated that the PGRS domain is required to maintain the protein strongly associated with the non-soluble cellular fraction. These results suggest that the repetitive GGA-GGN repeats of the PGRS domain contain specific sequences that contribute to protein cellular localization and that polar localization might be a key step in the PE_PGRS30-dependent virulence mechanism. 相似文献
45.
Li X Wang Q Zheng Y Lv S Ning S Sun J Huang T Zheng Q Ren H Xu J Wang X Li Y 《Nucleic acids research》2011,39(22):e153
The identification of human cancer-related microRNAs (miRNAs) is important for cancer biology research. Although several identification methods have achieved remarkable success, they have overlooked the functional information associated with miRNAs. We present a computational framework that can be used to prioritize human cancer miRNAs by measuring the association between cancer and miRNAs based on the functional consistency score (FCS) of the miRNA target genes and the cancer-related genes. This approach proved successful in identifying the validated cancer miRNAs for 11 common human cancers with area under ROC curve (AUC) ranging from 71.15% to 96.36%. The FCS method had a significant advantage over miRNA differential expression analysis when identifying cancer-related miRNAs with a fine regulatory mechanism, such as miR-27a in colorectal cancer. Furthermore, a case study examining thyroid cancer showed that the FCS method can uncover novel cancer-related miRNAs such as miR-27a/b, which were showed significantly upregulated in thyroid cancer samples by qRT-PCR analysis. Our method can be used on a web-based server, CMP (cancer miRNA prioritization) and is freely accessible at http://bioinfo.hrbmu.edu.cn/CMP. This time- and cost-effective computational framework can be a valuable complement to experimental studies and can assist with future studies of miRNA involvement in the pathogenesis of cancers. 相似文献
46.
Leah Wetherill Dongbing Lai Emma C. Johnson Andrey Anokhin Lance Bauer Kathleen K. Bucholz Danielle M. Dick Ahmad R. Hariri Victor Hesselbrock Chella Kamarajan John Kramer Samuel Kuperman Jacquelyn L. Meyers John I. Nurnberger Jr Marc Schuckit Denise M. Scott Robert E. Taylor Jay Tischfield Bernice Porjesz Alison M. Goate Howard J. Edenberg Tatiana Foroud Ryan Bogdan Arpana Agrawal 《Genes, Brain & Behavior》2019,18(6)
Genetic influences on alcohol and drug dependence partially overlap, however, specific loci underlying this overlap remain unclear. We conducted a genome‐wide association study (GWAS) of a phenotype representing alcohol or illicit drug dependence (ANYDEP) among 7291 European‐Americans (EA; 2927 cases) and 3132 African‐Americans (AA: 1315 cases) participating in the family‐based Collaborative Study on the Genetics of Alcoholism. ANYDEP was heritable (h 2 in EA = 0.60, AA = 0.37). The AA GWAS identified three regions with genome‐wide significant (GWS; P < 5E‐08) single nucleotide polymorphisms (SNPs) on chromosomes 3 (rs34066662, rs58801820) and 13 (rs75168521, rs78886294), and an insertion‐deletion on chromosome 5 (chr5:141988181). No polymorphisms reached GWS in the EA. One GWS region (chromosome 1: rs1890881) emerged from a trans‐ancestral meta‐analysis (EA + AA) of ANYDEP, and was attributable to alcohol dependence in both samples. Four genes (AA: CRKL, DZIP3, SBK3; EA: P2RX6) and four sets of genes were significantly enriched within biological pathways for hemostasis and signal transduction. GWS signals did not replicate in two independent samples but there was weak evidence for association between rs1890881 and alcohol intake in the UK Biobank. Among 118 AA and 481 EA individuals from the Duke Neurogenetics Study, rs75168521 and rs1890881 genotypes were associated with variability in reward‐related ventral striatum activation. This study identified novel loci for substance dependence and provides preliminary evidence that these variants are also associated with individual differences in neural reward reactivity. Gene discovery efforts in non‐European samples with distinct patterns of substance use may lead to the identification of novel ancestry‐specific genetic markers of risk. 相似文献
47.
Stephen K. Burley Helen M. Berman Wah Chiu Wei Dai Justin W. Flatt Brian P. Hudson Jason T. Kaelber Sagar D. Khare Arkadiusz W. Kulczyk Catherine L. Lawson Grigore D. Pintilie Andrej Sali Brinda Vallat John D. Westbrook Jasmine Y. Young Christine Zardecki 《Biophysical reviews》2022,14(6):1281
As a discipline, structural biology has been transformed by the three-dimensional electron microscopy (3DEM) “Resolution Revolution” made possible by convergence of robust cryo-preservation of vitrified biological materials, sample handling systems, and measurement stages operating a liquid nitrogen temperature, improvements in electron optics that preserve phase information at the atomic level, direct electron detectors (DEDs), high-speed computing with graphics processing units, and rapid advances in data acquisition and processing software. 3DEM structure information (atomic coordinates and related metadata) are archived in the open-access Protein Data Bank (PDB), which currently holds more than 11,000 3DEM structures of proteins and nucleic acids, and their complexes with one another and small-molecule ligands (~ 6% of the archive). Underlying experimental data (3DEM density maps and related metadata) are stored in the Electron Microscopy Data Bank (EMDB), which currently holds more than 21,000 3DEM density maps. After describing the history of the PDB and the Worldwide Protein Data Bank (wwPDB) partnership, which jointly manages both the PDB and EMDB archives, this review examines the origins of the resolution revolution and analyzes its impact on structural biology viewed through the lens of PDB holdings. Six areas of focus exemplifying the impact of 3DEM across the biosciences are discussed in detail (icosahedral viruses, ribosomes, integral membrane proteins, SARS-CoV-2 spike proteins, cryogenic electron tomography, and integrative structure determination combining 3DEM with complementary biophysical measurement techniques), followed by a review of 3DEM structure validation by the wwPDB that underscores the importance of community engagement. 相似文献
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