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Ligands and binding

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https://www.readbyqxmd.com/read/29346617/riboswitching-with-ciprofloxacin-development-and-characterization-of-a-novel-rna-regulator
#1
Florian Groher, Cristina Bofill-Bosch, Christopher Schneider, Johannes Braun, Sven Jager, Katharina Geißler, Kay Hamacher, Beatrix Suess
RNA molecules play important and diverse regulatory roles in the cell. Inspired by this natural versatility, RNA devices are increasingly important for many synthetic biology applications, e.g. optimizing engineered metabolic pathways, gene therapeutics or building up complex logical units. A major advantage of RNA is the possibility of de novo design of RNA-based sensing domains via an in vitro selection process (SELEX). Here, we describe development of a novel ciprofloxacin-responsive riboswitch by in vitro selection and next-generation sequencing-guided cellular screening...
January 13, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29346393/computational-study-of-hiv-gp120-as-a-target-for-polyanionic-entry-inhibitors-exploiting-the-v3-loop-region
#2
Louis R Hollingsworth, Anne M Brown, Richard D Gandour, David R Bevan
Multiple approaches are being utilized to develop therapeutics to treat HIV infection. One approach is designed to inhibit entry of HIV into host cells, with a target being the viral envelope glycoprotein, gp120. Polyanionic compounds have been shown to be effective in inhibiting HIV entry, with a mechanism involving electrostatic interactions with the V3 loop of gp120 being proposed. In this study, we applied computational methods to elucidate molecular interactions between the repeat unit of the precisely alternating polyanion, Poly(4,4'-stilbenedicarboxylate-alt-maleic acid) (DCSti-alt-MA) and the V3 loop of gp120 from strains of HIV against which these polyanions were previously tested (IIIb, BaL, 92UG037, JR-CSF) as well as two strains for which gp120 crystal structures are available (YU2, 2B4C)...
2018: PloS One
https://www.readbyqxmd.com/read/29346071/identification-of-potential-inhibitors-against-nuclear-dam1-complex-subunit-ask1-of-candida-albicans-using-virtual-screening-and-md-simulations
#3
Himanshu Tripathi, Feroz Khan
Identification of hit compounds against specific target form the starting point for a drug discovery program. A consistent decline of new chemical entities (NCEs) in recent years prompted a challenge to explore newer approaches to discover potential hit compounds that in turn can be converted into leads, and ultimately drug with desired therapeutic efficacy. The vast amount of omics and activity data available in public databases offers an opportunity to identify novel targets and their potential inhibitors...
January 1, 2018: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/29345933/large-scale-functional-group-symmetry-adapted-perturbation-theory-on-graphical-processing-units
#4
Robert M Parrish, Keiran C Thompson, Todd J Martínez
Symmetry-adapted perturbation theory (SAPT) is a valuable method for analyzing intermolecular interactions. The functional group SAPT partition (F-SAPT) has been introduced to provide additional insight into the origins of noncovalent interactions. Until now, SAPT analysis has been too costly for large ligand-protein complexes where it could provide key insights for chemical modifications that might improve ligand binding. In this paper, we present a large-scale implementation of F-SAPT which is especially efficient when one of the interacting monomers is significantly larger than the other, as is usually the case for drug-protein interactions...
January 18, 2018: Journal of Chemical Theory and Computation
https://www.readbyqxmd.com/read/29345931/umbrella-sampling-and-x-ray-crystallographic-analysis-unveil-an-arg-asp-gate-facilitating-inhibitor-binding-inside-phosphopantetheine-adenylyltransferase-allosteric-cleft
#5
Abhisek Mondal, Rakesh Chatterjee, Saumen Datta
Phosphopantetheine adenylyltransferase (PPAT) is a rate limiting enzyme essential for biosynthesis of coenzyme A (CoA) which in turn is responsible to regulate the secretion of exotoxins via type III secretion system in Pseudomonas aeruginosa, causing severe health concerns ranging from nosocomial infections to respiratory failure. Acetyl Coenzyme A (AcCoA) is a newly reported inhibitor of PPAT, believed to regulate the cellular levels of CoA and thereby the pathogenesis. Very little is known so far regarding the mechanistic details of AcCoA binding inside PPAT binding cleft...
January 18, 2018: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/29345419/targeting-bcl2-gene-promoter-g-quadruplex-with-a-new-class-of-furopyridazinone-based-molecules
#6
Jussara Amato, Alessia Pagano, Domenica Capasso, Sonia Di Gaetano, Mariateresa Giustiniano, Ettore Novellino, Antonio Randazzo, Bruno Pagano
Targeting of G-quadruplex-forming DNA in BCL2 gene promoter to inhibit the expression of anti-apoptotic Bcl-2 protein represents an attractive opportunity in cancer treatment. So far, efforts made in the discovery of molecules able to target BCL2 G-quadruplex mainly succeeded in the identification of ligands with poor drug-like properties. Here, a small series of furo[2,3-d]pyridazin-4(5H)-one derivatives were evaluated as a new class of drug-like G-quadruplex-targeting compounds. Biophysical studies showed that two derivatives could effectively bind to BCL2 G-quadruplex with good selectivity...
January 18, 2018: ChemMedChem
https://www.readbyqxmd.com/read/29344086/correlation-of-structure-function-and-protein-dynamics-in-gh7-cellobiohydrolases-from-trichoderma-atroviride-t-reesei-and-t-harzianum
#7
Anna S Borisova, Elena V Eneyskaya, Suvamay Jana, Silke F Badino, Jeppe Kari, Antonella Amore, Magnus Karlsson, Henrik Hansson, Mats Sandgren, Michael E Himmel, Peter Westh, Christina M Payne, Anna A Kulminskaya, Jerry Ståhlberg
Background: The ascomycete fungus Trichoderma reesei is the predominant source of enzymes for industrial conversion of lignocellulose. Its glycoside hydrolase family 7 cellobiohydrolase (GH7 CBH) TreCel7A constitutes nearly half of the enzyme cocktail by weight and is the major workhorse in the cellulose hydrolysis process. The orthologs from Trichoderma atroviride (TatCel7A) and Trichoderma harzianum (ThaCel7A) show high sequence identity with TreCel7A, ~ 80%, and represent naturally evolved combinations of cellulose-binding tunnel-enclosing loop motifs, which have been suggested to influence intrinsic cellobiohydrolase properties, such as endo-initiation, processivity, and off-rate...
2018: Biotechnology for Biofuels
https://www.readbyqxmd.com/read/29343868/galectin-13-a-different-prototype-galectin-does-not-bind-%C3%AE-galacto-sides-and-forms-dimers-via-intermolecular-disulfide-bridges-between-cys-136-and-cys-138
#8
Jiyong Su, Yue Wang, Yunlong Si, Jin Gao, Chenyang Song, Linlin Cui, Runjie Wu, Guihua Tai, Yifa Zhou
During pregnancy, placental protein-13 (galectin-13) is highly expressed in the placenta and fetal tissue, and less so in maternal serum that is related to pre-eclampsia. To understand galectin-13 function at the molecular level, we solved its crystal structure and discovered that its dimer is stabilized by two disulfide bridges between Cys136 and Cys138 and six hydrogen bonds involving Val135, Val137, and Gln139. Native PAGE and gel filtration demonstrate that this is not a crystallization artifact because dimers also form in solution...
January 17, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29343833/dopamine-d3-receptor-antagonist-reveals-a-cryptic-pocket-in-aminergic-gpcrs
#9
Noelia Ferruz, Stefan Doerr, Michelle A Vanase-Frawley, Yaozhong Zou, Xiaomin Chen, Eric S Marr, Robin T Nelson, Bethany L Kormos, Travis T Wager, Xinjun Hou, Anabella Villalobos, Simone Sciabola, Gianni De Fabritiis
The recent increase in the number of X-ray crystal structures of G-protein coupled receptors (GPCRs) has been enabling for structure-based drug design (SBDD) efforts. These structures have revealed that GPCRs are highly dynamic macromolecules whose function is dependent on their intrinsic flexibility. Unfortunately, the use of static structures to understand ligand binding can potentially be misleading, especially in systems with an inherently high degree of conformational flexibility. Here, we show that docking a set of dopamine D3 receptor compounds into the existing eticlopride-bound dopamine D3 receptor (D3R) X-ray crystal structure resulted in poses that were not consistent with results obtained from site-directed mutagenesis experiments...
January 17, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29343798/structural-and-functional-insights-into-s-thiolation-of-human-serum-albumins
#10
Fumie Nakashima, Takahiro Shibata, Kohei Kamiya, Jun Yoshitake, Ryosuke Kikuchi, Tadashi Matsushita, Isao Ishii, Juan A Giménez-Bastida, Claus Schneider, Koji Uchida
Human serum albumin (HSA) is the most abundant serum protein, contributing to the maintenance of redox balance in the extracellular fluids. One single free cysteine residue at position 34 is believed to be a target of oxidation. However, the molecular details and functions of oxidized HSAs remain obscure. Here we analyzed serum samples from normal subjects and hyperlipidemia patients and observed an enhanced S-thiolation of HSA in the hyperlipidemia patients as compared to the control individuals. Both cysteine and homocysteine were identified as the low molecular weight thiols bound to the HSAs...
January 17, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29343622/enhanced-preclinical-antitumor-activity-of-m7824-a-bifunctional-fusion-protein-simultaneously-targeting-pd-l1-and-tgf-%C3%AE
#11
Yan Lan, Dong Zhang, Chunxiao Xu, Kenneth W Hance, Bo Marelli, Jin Qi, Huakui Yu, Guozhong Qin, Aroop Sircar, Vivian M Hernández, Molly H Jenkins, Rachel E Fontana, Amit Deshpande, George Locke, Helen Sabzevari, Laszlo Radvanyi, Kin-Ming Lo
Antibodies targeting immune checkpoints are emerging as potent and viable cancer therapies, but not all patients respond to these as single agents. Concurrently targeting additional immunosuppressive pathways is a promising approach to enhance immune checkpoint blockade, and bifunctional molecules designed to target two pathways simultaneously may provide a strategic advantage over the combination of two single agents. M7824 (MSB0011359C) is a bifunctional fusion protein composed of a monoclonal antibody against programmed death ligand 1 (PD-L1) fused to the extracellular domain of human transforming growth factor-β (TGF-β) receptor II, which functions as a "trap" for all three TGF-β isoforms...
January 17, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29343616/rapamycin-activates-tgf-receptor-independently-of-its-ligand-implications-for-endothelial-dysfunction
#12
Ayumi A Miyakawa, Thais Girao-Silva, Jose E Krieger, Elazer R Edelman
Rapamycin, the macrolide immunosuppressant and active pharmaceutic in drug-eluting stents (DES), has a well-recognized anti-proliferative action that involves inhibition of the mTOR pathway after binding to the cytosolic protein FKBP12. TGF receptor-type I (TGFRI) spontaneous activation is inhibited by the association with FKBP12. We hypothesized that rapamycin, in addition to inhibition of mTOR signaling, activates TGFRI independent of TGFb. Human umbilical vein endothelial cells (HUVEC) were treated with rapamycin (10nmoL/L) and/or TGF-b RI kinase inhibitor (TGFRIi, 100nmoL/L) for 24 hours...
January 17, 2018: Clinical Science (1979-)
https://www.readbyqxmd.com/read/29343553/molecular-mechanisms-of-biased-and-probe-dependent-signaling-at-cxcr3-induced-by-negative-allosteric-modulators
#13
Regine Brox, Lampros Milanos, Noureldin Saleh, Paul Baumeister, Armin Buschauer, Dagmar Hofmann, Markus R Heinrich, Timothy Clark, Nuska Tschammer
Our recent explorations of allosteric modulators (AMs) with improved properties resulted in the identification of two biased negative AMs, N-1-{[3-(4-Ethoxyphenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimi-din2yl]ethyl}-4-(4-fluorobutoxy)-N-[(1-methylpiperidin-4-yl)me-thyl}]butanamide (BD103) and {5-[(N-{1-[3-(4-ethoxyphenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl]ethyl-2-[4-fluoro-3-(trifluoromethyl)phenyl]acetamido)methyl]-2-fluorophenyl}boronic acid (BD064), that exhibited probe-dependent inhibition of the chemokine receptor CXCR3 signaling...
January 17, 2018: Molecular Pharmacology
https://www.readbyqxmd.com/read/29343060/direct-co2-addition-to-a-ni-0-co-species-allows-the-selective-generation-of-a-nickel-ii-carboxylate-with-expulsion-of-co
#14
Dipankar Sahoo, Changho Yoo, Yunho Lee
Addition of CO2 to a low-valent nickel species has been explored with a newly designed acriPNP pincer ligand (acriPNP- = 4,5-bis(diisopropylphosphino)-2,7,9,9-tetramethyl-9H-acridin-10-ide). This is a crucial step in understanding biological CO2 conver-sion to CO found in carbon monoxide dehydrogenase (CODH). A four-coordinate nickel(0) state was reliably accessed in the pres-ence of a CO ligand, which can be prepared from a stepwise reduction of a cationic {(acriPNP)Ni(II)-CO}+ species. All three Ni(II), Ni(I) and Ni(0) monocarbonyl species were cleanly isolated and spectroscopically characterized...
January 17, 2018: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29342970/the-possible-importance-of-%C3%AE-3-integrins-for-leukemogenesis-and-chemoresistance-in-acute-myeloid-leukemia
#15
REVIEW
Silje Johansen, Annette K Brenner, Sushma Bartaula-Brevik, Håkon Reikvam, Øystein Bruserud
Acute myeloid leukemia (AML) is an aggressive bone marrow malignancy where the immature leukemia cells communicate with neighboring cells through constitutive cytokine release and through their cell surface adhesion molecules. The primary AML cells express various integrins. These heterodimeric molecules containing an α and a β chain are cell surface molecules that bind extracellular matrix molecules, cell surface molecules and soluble mediators. The β3 integrin (ITGB3) chain can form heterodimers only with the two α chains αIIb and αV...
January 15, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29342882/implication-of-soluble-forms-of-cell-adhesion-molecules-in-infectious-disease-and-tumor-insights-from-transgenic-animal-models
#16
REVIEW
Etsuro Ono, Toshimitsu Uede
Cell adhesion molecules (CAMs) are surface ligands, usually glycoproteins, which mediate cell-to-cell adhesion. They play a critical role in maintaining tissue integrity and mediating migration of cells, and some of them also act as viral receptors. It has been known that soluble forms of the viral receptors bind to the surface glycoproteins of the viruses and neutralize them, resulting in inhibition of the viral entry into cells. Nectin-1 is one of important CAMs belonging to immunoglobulin superfamily and herpesvirus entry mediator (HVEM) is a member of the tumor necrosis factor (TNF) receptor family...
January 13, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29342326/mixed-fluorotryptophan-substitutions-at-the-same-residue-expand-the-versatility-of-%C3%A2-%C3%A2-f-protein-nmr-spectroscopy
#17
Calem Kenward, Kyungsoo Shin, Jan Rainey
The strategy of applying fluorine NMR to characterize ligand binding to a membrane protein prepared with mixtures of tryptophans substituted with F at different positions on the indole ring was tested. The ¹⁹F NMR behavior of 4-, 5-, 6-, and 7-fluorotryptophan were directly compared as a function of both micellar environment and fragment size for two overlapping apelin receptor (AR/APJ) segments - one with a single transmembrane (TM) helix and two tryptophan residues, the other with three TM helices and two additional tryptophan residues...
January 17, 2018: Chemistry: a European Journal
https://www.readbyqxmd.com/read/29342138/%C3%AE-klotho-is-a-non-enzymatic-molecular-scaffold-for-fgf23-hormone-signalling
#18
Gaozhi Chen, Yang Liu, Regina Goetz, Lili Fu, Seetharaman Jayaraman, Ming-Chang Hu, Orson W Moe, Guang Liang, Xiaokun Li, Moosa Mohammadi
The ageing suppressor α-klotho binds to the fibroblast growth factor receptor (FGFR). This commits FGFR to respond to FGF23, a key hormone in the regulation of mineral ion and vitamin D homeostasis. The role and mechanism of this co-receptor are unknown. Here we present the atomic structure of a 1:1:1 ternary complex that consists of the shed extracellular domain of α-klotho, the FGFR1c ligand-binding domain, and FGF23. In this complex, α-klotho simultaneously tethers FGFR1c by its D3 domain and FGF23 by its C-terminal tail, thus implementing FGF23-FGFR1c proximity and conferring stability...
January 17, 2018: Nature
https://www.readbyqxmd.com/read/29342116/vegf-signaling-in-neurological-disorders
#19
REVIEW
Joon W Shim, Joseph R Madsen
Vascular endothelial growth factor (VEGF) is a potent growth factor playing diverse roles in vasculogenesis and angiogenesis. In the brain, VEGF mediates angiogenesis, neural migration and neuroprotection. As a permeability factor, excessive VEGF disrupts intracellular barriers, increases leakage of the choroid plexus endothelia, evokes edema, and activates the inflammatory pathway. Recently, we discovered that a heparin binding epidermal growth factor like growth factor (HB-EGF)-a class of EGF receptor (EGFR) family ligands-contributes to the development of hydrocephalus with subarachnoid hemorrhage through activation of VEGF signaling...
January 17, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29341876/probing-and-characterizing-the-high-specific-sequences-of-ssdna-aptamer-against-sgiv-infected-cells
#20
Pengfei Li, Qing Yu, Lingli Zhou, Dexin Dong, Shina Wei, Hanzheng Ya, Bo Chen, Qiwei Qin
As the major viral pathogen of grouper aquaculture, Singapore grouper iridovirus (SGIV) has caused great economic losses in China and Southeast Asia. In the previous study, we have generated highly specific ssDNA aptamers against SGIV-infected grouper spleen cells (GS) by Systematic Evolution of Ligands by Exponential Enrichment technology (SELEX), in which Q2 had the highest binding affinity of 16.43 nM. In this study, we would try to identify the specific sequences in the aptamer Q2 that exhibited the high binding affinity to SGIV-infected cells by truncating the original Q2 into some different specific segments...
January 13, 2018: Virus Research
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