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Cryo-EM

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https://www.readbyqxmd.com/read/28538735/ensemble-cryo-em-elucidates-the-mechanism-of-translation-fidelity
#1
Anna B Loveland, Gabriel Demo, Nikolaus Grigorieff, Andrei A Korostelev
Gene translation depends on accurate decoding of mRNA, the structural mechanism of which remains poorly understood. Ribosomes decode mRNA codons by selecting cognate aminoacyl-tRNAs delivered by elongation factor Tu (EF-Tu). Here we present high-resolution structural ensembles of ribosomes with cognate or near-cognate aminoacyl-tRNAs delivered by EF-Tu. Both cognate and near-cognate tRNA anticodons explore the aminoacyl-tRNA-binding site (A site) of an open 30S subunit, while inactive EF-Tu is separated from the 50S subunit...
May 24, 2017: Nature
https://www.readbyqxmd.com/read/28538729/cryo-em-structure-of-the-activated-glp-1-receptor-in-complex-with-a-g-protein
#2
Yan Zhang, Bingfa Sun, Dan Feng, Hongli Hu, Matthew Chu, Qianhui Qu, Jeffrey T Tarrasch, Shane Li, Tong Sun Kobilka, Brian K Kobilka, Georgios Skiniotis
Glucagon-like peptide 1 (GLP-1) is a hormone with essential roles in regulating insulin secretion, carbohydrate metabolism and appetite. GLP-1 effects are mediated through binding to the GLP-1 receptor (GLP-1R), a class B G-protein-coupled receptor (GPCR) that signals primarily through the stimulatory G protein Gs. Class B GPCRs are important therapeutic targets; however, our understanding of their mechanism of action is limited by the lack of structural information on activated and full-length receptors. Here we report the cryo-electron microscopy structure of the peptide-activated GLP-1R-Gs complex at near atomic resolution...
May 24, 2017: Nature
https://www.readbyqxmd.com/read/28534504/crystal-structure-of-the-receptor-binding-domain-of-the-spike-glycoprotein-of-human-betacoronavirus-hku1
#3
Xiuyuan Ou, Hongxin Guan, Bo Qin, Zhixia Mu, Justyna A Wojdyla, Meitian Wang, Samuel R Dominguez, Zhaohui Qian, Sheng Cui
Human coronavirus (CoV) HKU1 is a pathogen causing acute respiratory illnesses and so far little is known about its biology. HKU1 virus uses its S1 subunit C-terminal domain (CTD) and not the N-terminal domain like other lineage A β-CoVs to bind to its yet unknown human receptor. Here we present the crystal structure of HKU1 CTD at 1.9 Å resolution. The structure consists of three subdomains: core, insertion and subdomain-1 (SD-1). While the structure of the core and SD-1 subdomains of HKU1 are highly similar to those of other β-CoVs, the insertion subdomain adopts a novel fold, which is largely invisible in the cryo-EM structure of the HKU1 S trimer...
May 23, 2017: Nature Communications
https://www.readbyqxmd.com/read/28532216/structural-insights-into-the-eukaryotic-transcription-initiation-machinery
#4
Eva Nogales, Robert K Louder, Yuan He
Eukaryotic gene transcription requires the assembly at the promoter of a large preinitiation complex (PIC) that includes RNA polymerase II (Pol II) and the general transcription factors TFIID, TFIIA, TFIIB, TFIIF, TFIIE, and TFIIH. The size and complexity of Pol II, TFIID, and TFIIH have precluded their reconstitution from heterologous systems, and purification relies on scarce endogenous sources. Together with their conformational flexibility and the transient nature of their interactions, these limitations had precluded structural characterization of the PIC...
May 22, 2017: Annual Review of Biophysics
https://www.readbyqxmd.com/read/28528669/modulation-of-ion-channels-by-cysteine-rich-peptides-from-sequence-to-structure
#5
Mehdi Mobli, Eivind A B Undheim, Lachlan D Rash
Venom peptides are natural ligands of ion channels and have been used extensively in pharmacological characterization of various ion channels and receptors. In this chapter, we survey all known venom peptide ion-channel modulators. Our survey reveals that the majority of venom peptides characterized to date target voltage-gated sodium or potassium channels. We further find that the majority of these peptides are found in scorpion and spider venoms. We discuss the influence of the pharmacological tools available in biasing discovery and the classical "toxin-to-sequence" approach to venom peptide biodiscovery...
2017: Advances in Pharmacology
https://www.readbyqxmd.com/read/28528643/a-new-method-for-cryo-sectioning-cell-monolayers-using-a-correlative-workflow
#6
Androniki Kolovou, Martin Schorb, Abul Tarafder, Carsten Sachse, Yannick Schwab, Rachel Santarella-Mellwig
Cryo-electron microscopy (cryo-EM) techniques have made a huge advancement recently, providing close to atomic resolution of the structure of protein complexes. Interestingly, this imaging technique can be performed in cells, giving access to the molecular machines in their natural context, therefore bridging structural and cell biology. However, in situ structural electron microscopy faces one major challenge, which is the ability to focus on specific subcellular regions to capture the objects of interest...
2017: Methods in Cell Biology
https://www.readbyqxmd.com/read/28528306/the-group-ii-intron-maturase-a-reverse-transcriptase-and-splicing-factor-go-hand-in-hand
#7
REVIEW
Chen Zhao, Anna Marie Pyle
The splicing of group II introns in vivo requires the assistance of a multifunctional intron encoded protein (IEP, or maturase). Each IEP is also a reverse-transcriptase enzyme that enables group II introns to behave as mobile genetic elements. During splicing or retro-transposition, each group II intron forms a tight, specific complex with its own encoded IEP, resulting in a highly reactive holoenzyme. This review focuses on the structural basis for IEP function, as revealed by recent crystal structures of an IEP reverse transcriptase domain and cryo-EM structures of an IEP-intron complex...
May 18, 2017: Current Opinion in Structural Biology
https://www.readbyqxmd.com/read/28512576/applications-of-contact-predictions-to-structural-biology
#8
REVIEW
Felix Simkovic, Sergey Ovchinnikov, David Baker, Daniel J Rigden
Evolutionary pressure on residue interactions, intramolecular or intermolecular, that are important for protein structure or function can lead to covariance between the two positions. Recent methodological advances allow much more accurate contact predictions to be derived from this evolutionary covariance signal. The practical application of contact predictions has largely been confined to structural bioinformatics, yet, as this work seeks to demonstrate, the data can be of enormous value to the structural biologist working in X-ray crystallo-graphy, cryo-EM or NMR...
May 1, 2017: IUCrJ
https://www.readbyqxmd.com/read/28510023/protein-rna-interactions-structural-biology-and-computational-modeling-techniques
#9
REVIEW
Susan Jones
RNA-binding proteins are functionally diverse within cells, being involved in RNA-metabolism, translation, DNA damage repair, and gene regulation at both the transcriptional and post-transcriptional levels. Much has been learnt about their interactions with RNAs through structure determination techniques and computational modeling. This review gives an overview of the structural data currently available for protein-RNA complexes, and discusses the technical issues facing structural biologists working to solve their structures...
December 2016: Biophysical Reviews
https://www.readbyqxmd.com/read/28508083/structures-of-closed-and-open-conformations-of-dimeric-human-atm
#10
Domagoj Baretić, Hannah K Pollard, David I Fisher, Christopher M Johnson, Balaji Santhanam, Caroline M Truman, Tomas Kouba, Alan R Fersht, Christopher Phillips, Roger L Williams
ATM (ataxia-telangiectasia mutated) is a phosphatidylinositol 3-kinase-related protein kinase (PIKK) best known for its role in DNA damage response. ATM also functions in oxidative stress response, insulin signaling, and neurogenesis. Our electron cryomicroscopy (cryo-EM) suggests that human ATM is in a dynamic equilibrium between closed and open dimers. In the closed state, the PIKK regulatory domain blocks the peptide substrate-binding site, suggesting that this conformation may represent an inactive or basally active enzyme...
May 2017: Science Advances
https://www.readbyqxmd.com/read/28508067/cryo-em-structure-of-human-adenovirus-d26-reveals-the-conservation-of-structural-organization-among-human-adenoviruses
#11
Xiaodi Yu, David Veesler, Melody G Campbell, Mary E Barry, Francisco J Asturias, Michael A Barry, Vijay S Reddy
Human adenoviruses (HAdVs) cause acute respiratory, ocular, and gastroenteric diseases and are also frequently used as gene and vaccine delivery vectors. Unlike the archetype human adenovirus C5 (HAdV-C5), human adenovirus D26 (HAdV-D26) belongs to species-D HAdVs, which target different cellular receptors, and is differentially recognized by immune surveillance mechanisms. HAdV-D26 is being championed as a lower seroprevalent vaccine and oncolytic vector in preclinical and human clinical studies. To understand the molecular basis for their distinct biological properties and independently validate the structures of minor proteins, we determined the first structure of species-D HAdV at 3...
May 2017: Science Advances
https://www.readbyqxmd.com/read/28505348/implication-of-the-box-c-d-snornp-assembly-factor-rsa1p-in-u3-snornp-assembly
#12
Benjamin Rothé, Xavier Manival, Nicolas Rolland, Christophe Charron, Véronique Senty-Ségault, Christiane Branlant, Bruno Charpentier
The U3 box C/D snoRNA is one key element of 90S pre-ribosome. It contains a 5΄ domain pairing with pre-rRNA and the U3B/C and U3C΄/D motifs for U3 packaging into a unique small nucleolar ribonucleoprotein particle (snoRNP). The RNA-binding protein Snu13/SNU13 nucleates on U3B/C the assembly of box C/D proteins Nop1p/FBL and Nop56p/NOP56, and the U3-specific protein Rrp9p/U3-55K. Snu13p/SNU13 has a much lower affinity for U3C΄/D but nevertheless forms on this motif an RNP with box C/D proteins Nop1p/FBL and Nop58p/NOP58...
May 13, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28502770/an-atomic-structure-of-the-human-spliceosome
#13
Xiaofeng Zhang, Chuangye Yan, Jing Hang, Lorenzo I Finci, Jianlin Lei, Yigong Shi
Mechanistic understanding of pre-mRNA splicing requires detailed structural information on various states of the spliceosome. Here we report the cryo electron microscopy (cryo-EM) structure of the human spliceosome just before exon ligation (the C(∗) complex) at an average resolution of 3.76 Å. The splicing factor Prp17 stabilizes the active site conformation. The step II factor Slu7 adopts an extended conformation, binds Prp8 and Cwc22, and is poised for selection of the 3'-splice site. Remarkably, the intron lariat traverses through a positively charged central channel of RBM22; this unusual organization suggests mechanisms of intron recruitment, confinement, and release...
May 18, 2017: Cell
https://www.readbyqxmd.com/read/28500531/tubulin-like-proteins-in-prokaryotic-dna-positioning
#14
Gero Fink, Christopher H S Aylett
A family of tubulin-related proteins (TubZs) has been identified in prokaryotes as being important for the inheritance of virulence plasmids of several pathogenic Bacilli and also being implicated in the lysogenic life cycle of several bacteriophages. Cell biological studies and reconstitution experiments revealed that TubZs function as prokaryotic cytomotive filaments, providing one-dimensional motive forces. Plasmid-borne TubZ filaments most likely transport plasmid centromeric complexes by depolymerisation, pulling on the plasmid DNA, in vitro...
2017: Sub-cellular Biochemistry
https://www.readbyqxmd.com/read/28499500/ca-2-release-channels-join-the-resolution-revolution
#15
REVIEW
Ran Zalk, Andrew R Marks
Ryanodine receptors (RyRs) are calcium release channels expressed in the sarcoendoplasmic reticula of many cell types including cardiac and skeletal muscle cells. In recent years Ca(2+) leak through RyRs has been implicated as a major contributor to the development of diseases including heart failure, muscle myopathies, Alzheimer's disease, and diabetes, making it an important therapeutic target. Recent mammalian RyR1 cryoelectron microscopy (cryo-EM) structures of multiple functional states have clarified longstanding questions including the architecture of the transmembrane (TM) pore and cytoplasmic domains, the location and architecture of the channel gate, ligand-binding sites, and the gating mechanism...
May 9, 2017: Trends in Biochemical Sciences
https://www.readbyqxmd.com/read/28487427/structural-basis-for-linezolid-binding-site-rearrangement-in-the-staphylococcus-aureus-ribosome
#16
Matthew J Belousoff, Zohar Eyal, Mazdak Radjainia, Tofayel Ahmed, Rebecca S Bamert, Donna Matzov, Anat Bashan, Ella Zimmerman, Satabdi Mishra, David Cameron, Hans Elmlund, Anton Y Peleg, Shashi Bhushan, Trevor Lithgow, Ada Yonath
An unorthodox, surprising mechanism of resistance to the antibiotic linezolid was revealed by cryo-electron microscopy (cryo-EM) in the 70S ribosomes from a clinical isolate of Staphylococcus aureus This high-resolution structural information demonstrated that a single amino acid deletion in ribosomal protein uL3 confers linezolid resistance despite being located 24 Å away from the linezolid binding pocket in the peptidyl-transferase center. The mutation induces a cascade of allosteric structural rearrangements of the rRNA that ultimately results in the alteration of the antibiotic binding site...
May 9, 2017: MBio
https://www.readbyqxmd.com/read/28483196/bacterially-expressed-human-papillomavirus-type-6-and-11-bivalent-vaccine-characterization-antigenicity-and-immunogenicity
#17
Huirong Pan, Zhihai Li, Jin Wang, Shuo Song, Daning Wang, Minxi Wei, Ying Gu, Jun Zhang, Shaowei Li, Ningshao Xia
Human papillomavirus (HPV)-6 and HPV11 are the major etiological causes of condylomata acuminate. HPV neutralization by vaccine-elicited neutralizing antibodies can block viral infection and prevent subsequent disease. Currently, two commercially available HPV vaccines cover these two genotypes, expressed by Saccharomyces cerevisiae. Here we describe another HPV6/11 bivalent vaccine candidate derived from Escherichia coli. The soluble expression of N-terminally truncated L1 proteins was optimized to generate HPV6- and HPV11 L1-only virus-like particles (VLPs) as a scalable process...
May 31, 2017: Vaccine
https://www.readbyqxmd.com/read/28482099/rsga-couples-the-maturation-state-of-the-30s-ribosomal-decoding-center-to-activation-of-its-gtpase-pocket
#18
Jorge Pedro López-Alonso, Tatsuya Kaminishi, Takeshi Kikuchi, Yuya Hirata, Idoia Iturrioz, Neha Dhimole, Andreas Schedlbauer, Yoichi Hase, Simon Goto, Daisuke Kurita, Akira Muto, Shu Zhou, Chieko Naoe, Deryck J Mills, David Gil-Carton, Chie Takemoto, Hyouta Himeno, Paola Fucini, Sean R Connell
During 30S ribosomal subunit biogenesis, assembly factors are believed to prevent accumulation of misfolded intermediate states of low free energy that slowly convert into mature 30S subunits, namely, kinetically trapped particles. Among the assembly factors, the circularly permuted GTPase, RsgA, plays a crucial role in the maturation of the 30S decoding center. Here, directed hydroxyl radical probing and single particle cryo-EM are employed to elucidate RsgA's mechanism of action. Our results show that RsgA destabilizes the 30S structure, including late binding r-proteins, providing a structural basis for avoiding kinetically trapped assembly intermediates...
May 8, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28475873/structure-and-dynamics-of-a-197%C3%A2-bp-nucleosome-in-complex-with-linker-histone-h1
#19
Jan Bednar, Isabel Garcia-Saez, Ramachandran Boopathi, Amber R Cutter, Gabor Papai, Anna Reymer, Sajad H Syed, Imtiaz Nisar Lone, Ognyan Tonchev, Corinne Crucifix, Hervé Menoni, Christophe Papin, Dimitrios A Skoufias, Hitoshi Kurumizaka, Richard Lavery, Ali Hamiche, Jeffrey J Hayes, Patrick Schultz, Dimitar Angelov, Carlo Petosa, Stefan Dimitrov
Linker histones associate with nucleosomes to promote the formation of higher-order chromatin structure, but the underlying molecular details are unclear. We investigated the structure of a 197 bp nucleosome bearing symmetric 25 bp linker DNA arms in complex with vertebrate linker histone H1. We determined electron cryo-microscopy (cryo-EM) and crystal structures of unbound and H1-bound nucleosomes and validated these structures by site-directed protein cross-linking and hydroxyl radical footprinting experiments...
May 4, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28472657/structural-bases-of-desensitization-in-ampa-receptor-auxiliary-subunit-complexes
#20
Edward C Twomey, Maria V Yelshanskaya, Robert A Grassucci, Joachim Frank, Alexander I Sobolevsky
Fast excitatory neurotransmission is mediated by AMPA-subtype ionotropic glutamate receptors (AMPARs). AMPARs, localized at post-synaptic densities, are regulated by transmembrane auxiliary subunits that modulate AMPAR assembly, trafficking, gating, and pharmacology. Aberrancies in AMPAR-mediated signaling are associated with numerous neurological disorders. Here, we report cryo-EM structures of an AMPAR in complex with the auxiliary subunit GSG1L in the closed and desensitized states. GSG1L favors the AMPAR desensitized state, where channel closure is facilitated by profound structural rearrangements in the AMPAR extracellular domain, with ligand-binding domain dimers losing their local 2-fold rotational symmetry...
May 3, 2017: Neuron
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