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https://www.readbyqxmd.com/read/28934499/co-produced-natural-ketolides-methymycin-and-pikromycin-inhibit-bacterial-growth-by-preventing-synthesis-of-a-limited-number-of-proteins
#1
Mashal M Almutairi, Maxim S Svetlov, Douglas A Hansen, Nelli F Khabibullina, Dorota Klepacki, Han-Young Kang, David H Sherman, Nora Vázquez-Laslop, Yury S Polikanov, Alexander S Mankin
Antibiotics methymycin (MTM) and pikromycin (PKM), co-produced by Streptomyces venezuelae, represent minimalist macrolide protein synthesis inhibitors. Unlike other macrolides, which carry several side chains, a single desosamine sugar is attached to the macrolactone ring of MTM and PKM. In addition, the macrolactone scaffold of MTM is smaller than in other macrolides. The unusual structure of MTM and PKM and their simultaneous secretion by S. venezuelae bring about the possibility that two compounds would bind to distinct ribosomal sites...
September 19, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28934493/ubalai-is-a-monomeric-type-iie-restriction-enzyme
#2
Giedrius Sasnauskas, Giedre Tamulaitiene, Gintautas Tamulaitis, Jelena Calyševa, Migle Laime, Renata Rimšeliene, Arvydas Lubys, Virginijus Siksnys
Type II restriction endonucleases (REases) form a large and highly diverse group of enzymes. Even REases specific for a common recognition site often vary in their oligomeric structure, domain organization and DNA cleavage mechanisms. Here we report biochemical and structural characterization of the monomeric restriction endonuclease UbaLAI, specific for the pseudosymmetric DNA sequence 5'-CC/WGG-3' (where W = A/T, and '/' marks the cleavage position). We present a 1.6 Å co-crystal structure of UbaLAI N-terminal domain (UbaLAI-N) and show that it resembles the B3-family domain of EcoRII specific for the 5'-CCWGG-3' sequence...
September 19, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28934490/number-of-inadvertent-rna-targets-for-morpholino-knockdown-in-danio-rerio-is-largely-underestimated-evidence-from-the-study-of-ser-arg-rich-splicing-factors
#3
Marine Joris, Marie Schloesser, Denis Baurain, Marc Hanikenne, Marc Muller, Patrick Motte
Although the involvement of Ser/Arg-rich (SR) proteins in RNA metabolism is well documented, their role in vertebrate development remains elusive. We, therefore, elected to take advantage of the zebrafish model organism to study the SR genes' functions using the splicing morpholino (sMO) microinjection and the programmable site-specific nucleases. Consistent with previous research, we revealed discrepancies between the mutant and morphant phenotypes and we show that these inconsistencies may result from a large number of unsuspected inadvertent morpholino RNA targets...
September 19, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28934486/stn1-pola2-interaction-provides-a-basis-for-primase-pol-%C3%AE-stimulation-by-human-stn1
#4
Swapna Ganduri, Neal F Lue
The CST (CTC1-STN1-TEN1) complex mediates critical functions in maintaining telomere DNA and overcoming genome-wide replication stress. A conserved biochemical function of the CST complex is its primase-Pol α (PP) stimulatory activity. In this report, we demonstrate the ability of purified human STN1 alone to promote PP activity in vitro. We show that this regulation is mediated primarily by the N-terminal OB fold of STN1, but does not require the DNA-binding activity of this domain. Rather, we observed a strong correlation between the PP-stimulatory activity of STN1 variants and their abilities to bind POLA2...
September 19, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28934482/mechanistic-insight-into-how-multidrug-resistant-acinetobacter-baumannii-response-regulator-ader-recognizes-an-intercistronic-region
#5
Yurong Wen, Zhenlin Ouyang, Yue Yu, Xiaorong Zhou, Yingmei Pei, Bart Devreese, Paul G Higgins, Fang Zheng
AdeR-AdeS is a two-component regulatory system, which controls expression of the adeABC efflux pump involved in Acinetobacter baumannii multidrug resistance. AdeR is a response regulator consisting of an N-terminal receiver domain and a C-terminal DNA-binding-domain. AdeR binds to a direct-repeat DNA in the intercistronic region between adeR and adeABC. We demonstrate a markedly high affinity binding between unphosphorylated AdeR and DNA with a dissociation constant of 20 nM. In addition, we provide a 2.75 Å crystal structure of AdeR DNA-binding-domain complexed with the intercistronic DNA...
September 19, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28934473/the-conserved-au-dinucleotide-at-the-5-end-of-nascent-u1-snrna-is-optimized-for-the-interaction-with-nuclear-cap-binding-complex
#6
Chung-Shu Yeh, Shang-Lin Chang, Jui-Hui Chen, Hsuan-Kai Wang, Yue-Chang Chou, Chun-Hsiung Wang, Shih-Hsin Huang, Amy Larson, Jeffrey A Pleiss, Wei-Hau Chang, Tien-Hsien Chang
Splicing is initiated by a productive interaction between the pre-mRNA and the U1 snRNP, in which a short RNA duplex is established between the 5' splice site of a pre-mRNA and the 5' end of the U1 snRNA. A long-standing puzzle has been why the AU dincucleotide at the 5'-end of the U1 snRNA is highly conserved, despite the absence of an apparent role in the formation of the duplex. To explore this conundrum, we varied this AU dinucleotide into all possible permutations and analyzed the resulting molecular consequences...
September 19, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28934472/controlled-re-activation-of-epigenetically-silenced-tet-promoter-driven-transgene-expression-by-targeted-demethylation
#7
Natascha Gödecke, Lisha Zha, Shawal Spencer, Sara Behme, Pamela Riemer, Michael Rehli, Hansjörg Hauser, Dagmar Wirth
Faithful expression of transgenes in cell cultures and mice is often challenged by locus dependent epigenetic silencing. We investigated silencing of Tet-controlled expression cassettes within the mouse ROSA26 locus. We observed pronounced DNA methylation of the Tet promoter concomitant with loss of expression in mES cells as well as in differentiated cells and transgenic animals. Strikingly, the ROSA26 promoter remains active and methylation free indicating that this silencing mechanism specifically affects the transgene, but does not spread to the host's chromosomal neighborhood...
September 19, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28934471/a-novel-non-canonical-pip-box-mediates-parg-interaction-with-pcna
#8
Tanja Kaufmann, Irina Grishkovskaya, Anton A Polyansky, Sebastian Kostrhon, Eva Kukolj, Karin M Olek, Sebastien Herbert, Etienne Beltzung, Karl Mechtler, Thomas Peterbauer, Josef Gotzmann, Lijuan Zhang, Markus Hartl, Bojan Zagrovic, Kareem Elsayad, Kristina Djinovic-Carugo, Dea Slade
Poly(ADP-ribose) glycohydrolase (PARG) regulates cellular poly(ADP-ribose) (PAR) levels by rapidly cleaving glycosidic bonds between ADP-ribose units. PARG interacts with proliferating cell nuclear antigen (PCNA) and is strongly recruited to DNA damage sites in a PAR- and PCNA-dependent fashion. Here we identified PARG acetylation site K409 that is essential for its interaction with PCNA, its localization within replication foci and its recruitment to DNA damage sites. We found K409 to be part of a non-canonical PIP-box within the PARG disordered regulatory region...
September 19, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28934470/monitoring-replication-protein-a-rpa-dynamics-in-homologous-recombination-through-site-specific-incorporation-of-non-canonical-amino-acids
#9
Nilisha Pokhrel, Sofia Origanti, Eric Parker Davenport, Disha Gandhi, Kyle Kaniecki, Ryan A Mehl, Eric C Greene, Chris Dockendorff, Edwin Antony
An essential coordinator of all DNA metabolic processes is Replication Protein A (RPA). RPA orchestrates these processes by binding to single-stranded DNA (ssDNA) and interacting with several other DNA binding proteins. Determining the real-time kinetics of single players such as RPA in the presence of multiple DNA processors to better understand the associated mechanistic events is technically challenging. To overcome this hurdle, we utilized non-canonical amino acids and bio-orthogonal chemistry to site-specifically incorporate a chemical fluorophore onto a single subunit of heterotrimeric RPA...
September 19, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28934469/hnrnp-l-controls-hpv16-rna-polyadenylation-and-splicing-in-an-akt-kinase-dependent-manner
#10
Naoko Kajitani, Jacob Glahder, Chengjun Wu, Haoran Yu, Kersti Nilsson, Stefan Schwartz
Inhibition of the Akt kinase activates HPV16 late gene expression by reducing HPV16 early polyadenylation and by activating HPV16 late L1 mRNA splicing. We identified 'hot spots' for RNA binding proteins at the early polyA signal and at splice sites on HPV16 late mRNAs. We observed that hnRNP L was associated with sequences at all HPV16 late splice sites and at the early polyA signal. Akt kinase inhibition resulted in hnRNP L dephosphorylation and reduced association of hnRNP L with HPV16 mRNAs. This was accompanied by an increased binding of U2AF65 and Sam68 to HPV16 mRNAs...
September 19, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28934468/alyref-mainly-binds-to-the-5-and-the-3-regions-of-the-mrna-in-vivo
#11
Min Shi, Heng Zhang, Xudong Wu, Zhisong He, Lantian Wang, Shanye Yin, Bin Tian, Guohui Li, Hong Cheng
The TREX complex (TREX) plays key roles in nuclear export of mRNAs. However, little is known about its transcriptome-wide binding targets. We used individual cross-linking and immunoprecipitation (iCLIP) to identify the binding sites of ALYREF, an mRNA export adaptor in TREX, in human cells. Consistent with previous in vitro studies, ALYREF binds to a region near the 5' end of the mRNA in a CBP80-dependent manner. Unexpectedly, we identified PABPN1-dependent ALYREF binding near the 3' end of the mRNA. Furthermore, the 3' processing factor CstF64 directly interacts with ALYREF and is required for the overall binding of ALYREF on the mRNA...
September 19, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28934464/recruitment-and-delivery-of-the-fission-yeast-rst2-transcription-factor-via-a-local-genome-structure-counteracts-repression-by-tup1-family-corepressors
#12
Ryuta Asada, Miki Umeda, Akira Adachi, Satoshi Senmatsu, Takuya Abe, Hiroshi Iwasaki, Kunihiro Ohta, Charles S Hoffman, Kouji Hirota
Transcription factors (TFs) determine the transcription activity of target genes and play a central role in controlling the transcription in response to various environmental stresses. Three dimensional genome structures such as local loops play a fundamental role in the regulation of transcription, although the link between such structures and the regulation of TF binding to cis-regulatory elements remains to be elucidated. Here, we show that during transcriptional activation of the fission yeast fbp1 gene, binding of Rst2 (a critical C2H2 zinc-finger TF) is mediated by a local loop structure...
September 19, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28934292/hawaiian-skirt-controls-size-and-floral-organ-number-by-modulating-cuc1-and-cuc2-expression
#13
Zinnia H González-Carranza, Xuebin Zhang, Janny L Peters, Veronique Boltz, Judit Szecsi, Mohammed Bendahmane, Jeremy A Roberts
The Arabidopsis thaliana F-box gene HAWAIIAN SKIRT (HWS) affects organ growth and the timing of floral organ abscission. The loss-of-function hws-1 mutant exhibits fused sepals and increased organ size. To understand the molecular mechanisms of HWS during plant development, we mutagenized hws-1 seeds with ethylmethylsulphonate (EMS) and screened for mutations suppressing hws-1 associated phenotypes. We isolated the shs1/hws-1 (suppressor of hws-1) mutant in which hws-1 sepal fusion phenotype was suppressed...
2017: PloS One
https://www.readbyqxmd.com/read/28934246/discovery-of-pf-06928215-as-a-high-affinity-inhibitor-of-cgas-enabled-by-a-novel-fluorescence-polarization-assay
#14
Justin Hall, Amy Brault, Fabien Vincent, Shawn Weng, Hong Wang, Darren Dumlao, Ann Aulabaugh, Dikran Aivazian, Dana Castro, Ming Chen, Jeffrey Culp, Ken Dower, Joseph Gardner, Steven Hawrylik, Douglas Golenbock, David Hepworth, Mark Horn, Lyn Jones, Peter Jones, Eicke Latz, Jing Li, Lih-Ling Lin, Wen Lin, David Lin, Frank Lovering, Nootaree Niljanskul, Ryan Nistler, Betsy Pierce, Olga Plotnikova, Daniel Schmitt, Suman Shanker, James Smith, William Snyder, Timothy Subashi, John Trujillo, Edyta Tyminski, Guoxing Wang, Jimson Wong, Bruce Lefker, Leslie Dakin, Karen Leach
Cyclic GMP-AMP synthase (cGAS) initiates the innate immune system in response to cytosolic dsDNA. After binding and activation from dsDNA, cGAS uses ATP and GTP to synthesize 2', 3' -cGAMP (cGAMP), a cyclic dinucleotide second messenger with mixed 2'-5' and 3'-5' phosphodiester bonds. Inappropriate stimulation of cGAS has been implicated in autoimmune disease such as systemic lupus erythematosus, thus inhibition of cGAS may be of therapeutic benefit in some diseases; however, the size and polarity of the cGAS active site makes it a challenging target for the development of conventional substrate-competitive inhibitors...
2017: PloS One
https://www.readbyqxmd.com/read/28934144/the-recognition-of-calmodulin-to-the-target-sequence-of-calcineurin-a-novel-binding-mode
#15
Chia-Lin Chyan, Deli Irene, Sin-Mao Lin
Calcineurin (CaN) is a Ca(2+)/calmodulin-dependent Ser/Thr protein phosphatase, which plays essential roles in many cellular and developmental processes. CaN comprises two subunits, a catalytic subunit (CaN-A, 60 kDa) and a regulatory subunit (CaN-B, 19 kDa). CaN-A tightly binds to CaN-B in the presence of minimal levels of Ca(2+), but the enzyme is inactive until activated by CaM. Upon binding to CaM, CaN then undergoes a conformational rearrangement, the auto inhibitory domain is displaced and thus allows for full activity...
September 21, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28934103/investigating-the-interaction-of-cyclic-rgd-peptidomimetics-with-%C3%AE-v%C3%AE-%C3%A2-integrin-by-biochemical-and-molecular-docking-studies
#16
Monica Civera, Daniela Arosio, Francesca Bonato, Leonardo Manzoni, Luca Pignataro, Simone Zanella, Cesare Gennari, Umberto Piarulli, Laura Belvisi
The interaction of a small library of cyclic RGD (Arg-Gly-Asp) peptidomimetics with αVβ₆ integrin has been investigated by means of competitive solid phase binding assays to the isolated receptor and docking calculations in the crystal structure of the αVβ₆ binding site. To this aim, a rigid receptor-flexible ligand docking protocol has been set up and then applied to predict the binding mode of the cyclic RGD peptidomimetics to αVβ₆ integrin. Although the RGD interaction with αVβ₆ recapitulates the RGD binding mode observed in αVβ₃, differences between the integrin binding pockets can strongly affect the ligand binding ability...
September 21, 2017: Cancers
https://www.readbyqxmd.com/read/28933844/mind-the-metal-a-fragment-library-derived-zinc-impurity-binds-the-e2-ubiquitin-conjugating-enzyme-ube2t-and-induces-structural-rearrangements
#17
Francesca E Morreale, Andrea Testa, Viduth K Chaugule, Alessio Bortoluzzi, Alessio Ciulli, Helen Walden
Efforts to develop inhibitors, activators and effectors of biological reactions using small molecule libraries are often hampered by interference compounds, artifacts and false positives that permeate the pool of initial hits. Here we report the discovery of a promising initial hit compound targeting the Fanconi anemia ubiquitin-conjugating enzyme Ube2T and describe its biophysical and biochemical characterization. Analysis of the co-crystal structure led to the identification of a contaminating zinc ion as solely responsible for the observed effects...
September 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28933746/evaluation-of-novel-dual-acetyl-and-butyrylcholinesterase-inhibitors-as-potential-anti-alzheimer-s-disease-agents-using-pharmacophore-3d-qsar-and-molecular-docking-approaches
#18
Xiaocong Pang, Hui Fu, Shilun Yang, Lin Wang, Ai-Lin Liu, Song Wu, Guan-Hua Du
DL0410, containing biphenyl and piperidine skeletons, was identified as an acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitor through high-throughput screening assays, and further studies affirmed its efficacy and safety for Alzheimer's disease treatment. In our study, a series of novel DL0410 derivatives were evaluated for inhibitory activities towards AChE and BuChE. Among these derivatives, compounds 6-1 and 7-6 showed stronger AChE and BuChE inhibitory activities than DL0410. Then, pharmacophore modeling and three-dimensional quantitative structure activity relationship (3D-QSAR) models were performed...
July 26, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28933693/structural-inhibition-of-dynamin-mediated-membrane-fission-by-endophilin
#19
Annika Hohendahl, Nathaniel Talledge, Valentina Galli, Peter S Shen, Frédéric Humbert, Pietro De Camilli, Adam Frost, Aurélien Roux
Dynamin, which mediates membrane fission during endocytosis, binds endophilin and other members of the Bin-Amphiphysin-Rvs (BAR) protein family. How endophilin influences endocytic membrane fission is still unclear. Here we show that dynamin-mediated membrane fission is potently inhibited in vitro when an excess of endophilin co-assembles with dynamin around membrane tubules. We further show by electron microscopy that endophilin intercalates between turns of the dynamin helix and impairs fission by preventing trans interactions between dynamin rungs that are thought to play critical roles in membrane constriction...
September 21, 2017: ELife
https://www.readbyqxmd.com/read/28933593/dynein-promotes-porcine-oocyte-meiotic-progression-by-maintaining-cytoskeletal-structures-and-cortical-granule-arrangement
#20
Yilong Miao, Changyin Zhou, Zhaokang Cui, Liansheng Tang, Xiayan ShiYang, Yajuan Lu, Mianqun Zhang, Xiaoxin Dai, Bo Xiong
Cytoplasmic dynein is a family of cytoskeletal motor proteins that move towards the minus-end of the microtubules to perform functions in a variety of mitotic processes such as cargo transport, organelle positioning, chromosome movement and centrosome assembly. However, its specific roles during mammalian oocyte meiosis have not been fully defined. Herein, we investigated the critical events during porcine oocyte meiotic maturation after inhibition of dynein by Ciliobrevin D treatment. We found that oocyte meiotic progression was arrested when inhibited of dynein by showing the poor expansion of cumulus cells and decreased rate of polar body extrusion...
September 21, 2017: Cell Cycle
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