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https://www.readbyqxmd.com/read/28548638/asymmetric-recognition-of-hiv-1-envelope-trimer-by-v1v2-loop-targeting-antibodies
#1
Haoqing Wang, Harry B Gristick, Louise Scharf, Anthony P West, Rachel P Galimidi, Michael S Seaman, Natalia T Freund, Michel C Nussenzweig, Pamela J Bjorkman
The HIV-1 envelope (Env) glycoprotein binds to host cell receptors to mediate membrane fusion. The prefusion Env trimer is stabilized by V1V2 loops that interact at the trimer apex. Broadly neutralizing antibodies (bNAbs) against V1V2 loops, exemplified by PG9, bind asymmetrically as a single Fab to the apex of the symmetric Env trimer using a protruding CDRH3 to penetrate the Env glycan shield. Here we characterized a distinct mode of V1V2 epitope recognition by the new bNAb BG1 in which two Fabs bind asymmetrically per Env trimer using a compact CDRH3...
May 26, 2017: ELife
https://www.readbyqxmd.com/read/28541300/splicing-modulators-act-at-the-branch-point-adenosine-binding-pocket-defined-by-the-phf5a-sf3b-complex
#2
Teng Teng, Jennifer Hc Tsai, Xiaoling Puyang, Michael Seiler, Shouyong Peng, Sudeep Prajapati, Daniel Aird, Silvia Buonamici, Benjamin Caleb, Betty Chan, Laura Corson, Jacob Feala, Peter Fekkes, Baudouin Gerard, Craig Karr, Manav Korpal, Xiang Liu, Jason T Lowe, Yoshiharu Mizui, James Palacino, Eunice Park, Peter G Smith, Vanitha Subramanian, Zhenhua Jeremy Wu, Jian Zou, Lihua Yu, Agustin Chicas, Markus Warmuth, Nicholas Larsen, Ping Zhu
Pladienolide, herboxidiene and spliceostatin have been identified as splicing modulators that target SF3B1 in the SF3b subcomplex. Here we report that PHF5A, another component of this subcomplex, is also targeted by these compounds. Mutations in PHF5A-Y36, SF3B1-K1071, SF3B1-R1074 and SF3B1-V1078 confer resistance to these modulators, suggesting a common interaction site. RNA-seq analysis reveals that PHF5A-Y36C has minimal effect on basal splicing but inhibits the global action of splicing modulators. Moreover, PHF5A-Y36C alters splicing modulator-induced intron-retention/exon-skipping profile, which correlates with the differential GC content between adjacent introns and exons...
May 25, 2017: Nature Communications
https://www.readbyqxmd.com/read/28538735/ensemble-cryo-em-elucidates-the-mechanism-of-translation-fidelity
#3
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
#4
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/28536302/a-cryo-em-based-model-of-phosphorylation-and-fkbp12-6-mediated-allosterism-of-the-cardiac-ryanodine-receptor
#5
Sonali Dhindwal, Joshua Lobo, Vanessa Cabra, Demetrio J Santiago, Ashok R Nayak, Kelly Dryden, Montserrat Samsó
Type 2 ryanodine receptors (RyR2s) are calcium channels that play a vital role in triggering cardiac muscle contraction by releasing calcium from the sarcoplasmic reticulum into the cytoplasm. Several cardiomyopathies are associated with the abnormal functioning of RyR2. We determined the three-dimensional structure of rabbit RyR2 in complex with the regulatory protein FKBP12.6 in the closed state at 11.8 Å resolution using cryo-electron microscopy and built an atomic model of RyR2. The heterogeneity in the data set revealed two RyR2 conformations that we proposed to be related to the extent of phosphorylation of the P2 domain...
May 23, 2017: Science Signaling
https://www.readbyqxmd.com/read/28536299/new-connections-how-to-become-more-flexible-and-open-up
#6
Wei Wong
Cryo-EM-generated structures provide insight into how RyR2 is gated and how phosphorylation may affect the activation process.
May 23, 2017: Science Signaling
https://www.readbyqxmd.com/read/28534504/crystal-structure-of-the-receptor-binding-domain-of-the-spike-glycoprotein-of-human-betacoronavirus-hku1
#7
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
#8
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
#9
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
#10
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
#11
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
#12
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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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