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https://www.readbyqxmd.com/read/28108384/molecular-features-of-the-l-type-amino-acid-transporter-2-determine-different-import-and-export-profiles-for-thyroid-hormones-and-amino-acids
#1
Katrin M Hinz, Dominik Neef, Claudia Rutz, Jens Furkert, Josef Köhrle, Ralf Schülein, Gerd Krause
The L-type amino acid transporter 2 (LAT2) imports amino acids (AA) and also certain thyroid hormones (TH), e.g. 3,3'-T2 and T3, but not rT3 and T4. We utilized LAT2 mutations (Y130A, N133S, F242W) that increase 3,3'-T2 import and focus here on import and export capacity for AA, T4, T3, BCH and derivatives thereof to delineate molecular features. Transport studies and analysis of competitive inhibition of import by radiolabelled TH and AA were performed in Xenopus laevis oocytes. Only Y130A, a pocket widening mutation, enabled import for T4 and increased it for T3...
January 17, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28106222/digestibility-and-supramolecular-structural-changes-of-maize-starch-by-non-covalent-interactions-with-gallic-acid
#2
Chengdeng Chi, Xiaoxi Li, Yiping Zhang, Ling Chen, Lin Li, Zhijiang Wang
The effects of non-covalent interactions between gallic acid (GA) and starch on starch digestibility and supramolecular structural changes (short-range ordered molecular structure, crystalline structure, lamellar structure and fractal structure) were investigated. The results indicated that the digestibility of both starches was substantially reduced in the rapidly digestible starch (RDS) content, but resistant starch (RS) was increased after interacting with GA. The RS content of starch-GA complexes ranged from 17...
January 20, 2017: Food & Function
https://www.readbyqxmd.com/read/28096403/crystal-structure-of-pistol-a-class-of-self-cleaving-ribozyme
#3
Laura A Nguyen, Jimin Wang, Thomas A Steitz
Small self-cleaving ribozymes have been discovered in all evolutionary domains of life. They can catalyze site-specific RNA cleavage, and as a result, they have relevance in gene regulation. Comparative genomic analysis has led to the discovery of a new class of small self-cleaving ribozymes named Pistol. We report the crystal structure of Pistol at 2.97-Å resolution. Our results suggest that the Pistol ribozyme self-cleavage mechanism likely uses a guanine base in the active site pocket to carry out the phosphoester transfer reaction...
January 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28094221/synthesis-biological-evaluation-and-molecular-docking-analysis-of-2-phenyl-benzofuran-3-carboxamide-derivatives-as-potential-inhibitors-of-staphylococcus-aureus-sortase-a
#4
Wan He, Yong Zhang, Jian Bao, Xinxian Deng, Jennifer Batara, Shawn Casey, Qiuyuan Guo, Faqin Jiang, Lei Fu
In Gram-positive bacteria, Sortase A (Srt A) is a critical cysteine transpeptidase that is responsible for recognizing and assembling surface virulence proteins through the recognition of a LPXTG (leucine, proline, X, threonine, and glycine, where X is any amino acid) signal. Mutants lacking genes for Srt A attenuate infections without affecting microbial viability. Here a series of 2-phenyl-benzofuran-3-carboxamide derivatives were synthesized and identified as potent Srt A inhibitors. Activity assays revealed that multiple compounds exhibited excellent inhibitory activity against Srt A compared with known Sortase A inhibitor pHMB (IC50=130μM)...
December 25, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28091608/binding-of-n-methylscopolamine-to-the-extracellular-domain-of-muscarinic-acetylcholine-receptors
#5
Jan Jakubík, Alena Randáková, Pavel Zimčík, Esam E El-Fakahany, Vladimír Doležal
Interaction of orthosteric ligands with extracellular domain was described at several aminergic G protein-coupled receptors, including muscarinic acetylcholine receptors. The orthosteric antagonists quinuclidinyl benzilate (QNB) and N-methylscopolamine (NMS) bind to the binding pocket of the muscarinic acetylcholine receptor formed by transmembrane α-helices. We show that high concentrations of either QNB or NMS slow down dissociation of their radiolabeled species from all five subtypes of muscarinic acetylcholine receptors, suggesting allosteric binding...
January 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28088792/impact-of-nudt15-polymorphisms-on-thiopurines-induced-myelotoxicity-and-thiopurines-tolerance-dose
#6
Dandan Yin, Xuyang Xia, Junlong Zhang, Shouyue Zhang, Fei Liao, Ge Zhang, Yan Zhang, Qianqian Hou, Xue Yang, Hong Wang, Zhigui Ma, Heyao Wang, Yiping Zhu, Wei Zhang, Yuelan Wang, Bo Liu, Lanlan Wang, Heng Xu, Yang Shu
Thiopurines are widely used as anticancer and immunosuppressive agents. However, life-threatening myelotoxicity has been noticed and largely explained by genetic variations, including NUDT15 polymorphisms (e.g., rs116855232). In this study, we conduct a meta-analysis to investigate the impact of rs116855232 on thiopurines-induced myelotoxicity susceptibility (1752 patients from 7 independent cohorts), as well as on thiopurines intolerance dose (2745 patients from 13 cohorts). Variant allele of rs116855232 contributes 7...
January 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28069825/intravenous-anesthetic-propofol-binds-to-5-lipoxygenase-and-attenuates-leukotriene-b4-production
#7
Toshiaki Okuno, Sophia Koutsogiannaki, Mai Ohba, Matthew Chamberlain, Weiming Bu, Fu-Yan Lin, Roderic G Eckenhoff, Takehiko Yokomizo, Koichi Yuki
Propofol is an intravenous anesthetic that produces its anesthetic effect, largely via the GABAA receptor in the CNS, and also reduces the N-formyl-methionyl-leucyl-phenylalanine (fMLP)-induced neutrophil respiratory burst. Because fMLP-stimulated neutrophils produce leukotriene (LT)B4, we examined the effect of propofol on LTB4 production in vivo and in vitro Cecal ligation and puncture surgery was performed in mice, with or without exposure to propofol. Propofol attenuated the production of 5-lipoxygenase (5-LOX)-related arachidonic acid (AA) derivatives in the peritoneal fluid...
January 9, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28067452/expanding-the-catalytic-promiscuity-of-heparinase-iii-from-pedobacter-heparinus
#8
Yayun Gu, Meiling Lu, Zongqiang Wang, Xuri Wu, Yijun Chen
Glycosaminoglycans (GAG) lyases are useful biocatalysts for the preparation of oligosaccharides, but their substrate spectra are limited to the same family. Thus, the degradation activity across-families of GAG lyases is advantageous and desirable for various applications. In this study, residue Lys130 at the substrate entrance of monomeric heparinase III from Pedobacter heparinus ATCC 13125 was replaced by cysteine, and the resulting mutant K130C showed novel catalytic activity of degrading hyaluronic acid without affecting its native activity toward heparin and heparan sulfate...
January 9, 2017: Chemistry: a European Journal
https://www.readbyqxmd.com/read/28064376/docking-and-molecular-dynamics-studies-on-triclosan-derivatives-binding-to-fabi
#9
Xuyun Yang, Junrui Lu, Ming Ying, Jiangbei Mu, Peichun Li, Yue Liu
FabI, enoyl-ACP reductase (ENR), is the rate-limiting enzyme in the last step for fatty acids biosynthesis in many bacteria. Triclosan (TCL) is a commercial bactericide, and as a FabI inhibitor, it can depress the substrate (trans-2-enoyl-ACP) binding with FabI to hinder the fatty acid synthesis. The structure-activity relationship between TCL derivatives and FabI protein has already been acknowledged, however, their combination at the molecular level has never been investigated. This paper uses the computer-aided approaches, such as molecular docking, molecular dynamics simulation, and binding free energy calculation based on the molecular mechanics/Poisson-Bolzmann surface area (MM/PBSA) method to illustrate the interaction rules of TCL derivatives with FabI and guide the development of new derivatives...
January 2017: Journal of Molecular Modeling
https://www.readbyqxmd.com/read/28059502/chiral-nh-controlled-supramolecular-metallacycles
#10
Jinqiao Dong, Chunxia Tan, Kang Zhang, Yan Liu, Paul J Low, Jianwen Jiang, Yong Cui
Chiral NH functionalities-based discrimination is a key feature of Nature's chemical armory, yet selective binding of biologically active molecules in synthetic systems with high enantioselectivity poses significant challenges. Here we report the assembly of three chiral fluorescent Zn6L6 metallacycles from pyridyl-functionalized Zn(salalen) and/or Zn(salen) complexes. Each of these metallacycles has a nanoscale hydrophobic cavity decorated with six, three or zero chiral NH functionalities and packs into a three-dimensional supramolecular porous framework...
January 6, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28059499/inactivation-of-the-nuclear-orphan-receptor-coup-tfii-by-small-chemicals
#11
Rémy Le Guével, Frédérik Oger, Celia P Martinez-Jimenez, Maud Bizot, Céline Gheeraert, François Firmin, Maheul Ploton, Miroslava Kretova, Gaëlle Palierne, Bart Staels, Peter Barath, Iannis Talianidis, Philippe Lefebvre, Jérôme Eeckhoute, Gilles Salbert
Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII/NR2F2) is an orphan member of the nuclear receptor family of transcription factors whose activities are modulated upon binding of small molecules into an hydrophobic ligand-binding pocket (LBP). Although the LBP of COUP-TFII is filled with aromatic amino-acid side chains, alternative modes of ligand binding could potentially lead to regulation of the orphan receptor. Here, we screened a synthetic and natural compound library in a yeast one-hybrid assay and identified 4-methoxynaphthol as an inhibitor of COUP-TFII...
January 13, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28057757/oxidative-maturation-and-structural-characterization-of-prenylated-fmn-binding-by-ubid-a-decarboxylase-involved-in-bacterial-ubiquinone-biosynthesis
#12
Stephen A Marshall, Karl Fisher, Aisling Ni Cheallaigh, Mark D White, Karl A P Payne, D A Parker, Stephen E J Rigby, David Leys
The activity of the reversible decarboxylase enzyme Fdc1 is dependent on prenylated FMN (prFMN), a recently discovered cofactor. The oxidized prFMN supports a 1,3-dipolar cycloaddition mechanism that underpins reversible decarboxylation. Fdc1 is a distinct member of the UbiD family of enzymes, with the canonical UbiD catalyzing the (de)carboxylation of para-hydroxybenzoic acid-type substrates. Here we show that the Escherichia coli UbiD enzyme, which is implicated in ubiquinone biosynthesis, cannot be isolated in an active holo-enzyme form, despite the fact active holo-Fdc1 is readily obtained...
January 5, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28054779/n6-adenosine-dna-methyltransferase-from-h-pylori-98-10-strain-in-complex-with-dna-and-adomet-structural-insights-from-in-silico-studies
#13
Swati Singh, Lalitha Guruprasad
Helicobacter pylori is a primitive Gram-negative bacterium that resides in the acidic environment of the human gastrointestinal tract, and some strains of this bacterium cause gastric ulcers and cancer. DNA methyltransferases (MTases) are promising drug targets for the treatment of cancer and other diseases that are also caused by epigenetic alternations of the genome. The N6-adenine-specific DNA MTase from H. pylori (M. Hpy N6mA) catalyzes the transfer of a methyl group from the cofactor S-adenosyl-l-methionine (AdoMet) to the flipped adenine of the substrate DNA...
January 19, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28049370/underlying-molecular-interaction-of-bovine-serum-albumin-and-linezolid-a-biophysical-outlook
#14
Amartya Roy, Paromita Seal, Jyotirmoy Sikdar, Sanghamitra Banerjee, Rajen Haldar
Linezolid, one of the reserve antibiotic of oxazolidinone class has wide range of antimicrobial activity. Here we have conducted a fundamental study concerning the dynamics of its interaction with bovine serum albumin (BSA), and the post binding modification of the later by employing different spectroscopic (absorption, fluorescence and circular dichroism (CD) spectroscopy) and molecular docking tools. Gradual quenching of the tryptophan (Trp) fluorescence upon addition of linezolid to BSA confirms their interaction...
January 19, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28045264/exploring-the-mutational-robustness-of-nucleic-acids-by-searching-genotype-neighborhoods-in-sequence-space
#15
Qingtong Zhou, Xianbao Sun, Xiaole Xia, Zhou Fan, Zhaofeng Luo, Suwen Zhao, Eugene Shakhnovich, Haojun Liang
To assess the mutational robustness of nucleic acids, many genome- and protein-level studies have been performed, where nucleic acids are treated as genetic information carriers and transferrers. However, the molecular mechanisms through which mutations alter the structural, dynamic, and functional properties of nucleic acids are poorly understood. Here we performed a SELEX in silico study to investigate the fitness distribution of the l-Arm-binding aptamer genotype neighborhoods. Two novel functional genotype neighborhoods were isolated and experimentally verified to have comparable fitness as the wild-type...
January 19, 2017: Journal of Physical Chemistry Letters
https://www.readbyqxmd.com/read/28044941/design-synthesis-and-biological-evaluation-of-a-phenyl-butyric-acid-derivative-n-4-chlorophenyl-4-phenylbutanamide-a-hdac6-inhibitor-with-anti-proliferative-activity-on-cervix-cancer-and-leukemia-cells
#16
Rodríguez-Fonseca Rolando Alberto, Sixto-López Yudibeth, Fragoso-Vázquez M Jonathan, Flores-Mejía Raúl, Cabrera-Pérez Laura Cristina, Vázquez-Moctezuma Ismael, Rosales-Hernández Martha Cecilia, Bello Martiniano, M Martínez-Archundia, Trujillo-Ferrara José Guadalupe, Becerra-Martínez Elvia, Correa-Basurto José
The epigenetic regulation of genes in cancer could be targeted by inhibiting Histone deacetylase 6 (HDAC6), an enzyme involved in several types of cancer such as lymphoma, leukemia, ovarian cancer, etc. Through in silico methods, a set of Phenyl butyric acid derivatives with possible HDAC6 inhibitory activity were designed, rendering monophenylamides and biphenylamides using tubacin (HDAC6 selective inhibitor) as reference. The target compounds were submitted to theoretical ADMET analyses and their binding properties on different HDAC6 conformers were evaluated through docking calculations...
January 2, 2017: Anti-cancer Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/28044206/collapsin-response-mediator-protein-2-high-resolution-crystal-structure-sheds-light-on-small-molecule-binding-post-translational-modifications-and-conformational-flexibility
#17
Matti Myllykoski, Anne Baumann, Kenneth Hensley, Petri Kursula
Collapsin response mediator protein 2 (CRMP-2) is a neuronal protein involved in axonal pathfinding. Intense research is focusing on its role in various neurological diseases. Despite a wealth of studies, not much is known about the molecular mechanisms of CRMP-2 function in vivo. The detailed structure-function relationships of CRMP-2 have also largely remained unknown, in part due to the fact that the available crystal structures lack the C-terminal tail, which is known to be a target for many post-translational modifications and protein interactions...
January 2, 2017: Amino Acids
https://www.readbyqxmd.com/read/28043736/identification-of-amino-acids-in-antigen-binding-site-of-class-ii-hla-proteins-independently-associated-with-hepatitis-b-vaccine-response
#18
Aiko Sakai, Emiko Noguchi, Takashi Fukushima, Manabu Tagawa, Atsushi Iwabuchi, Masaki Kita, Keisuke Kakisaka, Akio Miyasaka, Yasuhiro Takikawa, Ryo Sumazaki
BACKGROUND & AIMS: Genetic factors in class II human leukocyte antigen (HLA) have been reported to be associated with inter-individual variation in hepatitis B virus (HBV) vaccine response. However, the mechanism underlying the associations remains elusive. In particular, the broad linkage disequilibrium in HLA region complicates the localization of the independent effects of genetic variants. Thus, the present study aimed to identify the most probable causal variations in class II HLA loci involved in the immune response to HBV vaccine...
December 30, 2016: Vaccine
https://www.readbyqxmd.com/read/28043639/identification-of-novel-mycobacterium-tuberculosis-dihydrofolate-reductase-inhibitors-through-rational-drug-design
#19
Mymoona Akhter
OBJECTIVES/BACKGROUND: Dihydrofolate reductase (DHFR) is one of the validated drug targets in Mycobacterium tuberculosis (Mtb) infection. DHFR inhibitors have been used to treat various life-threatening diseases such as cancer, malaria, and several bacterial infections. However, all clinically effective DHFR inhibitors are non-selective, and inhibit both human and pathogenic DHFRs more or less to a similar extent. The crystal structure of various DHFRs complexed with nicotinamide adenine dinucleotide phosphate and different inhibitors is available in the protein data bank...
December 2016: International Journal of Mycobacteriology
https://www.readbyqxmd.com/read/28040890/solid-state-nmr-structural-study-of-retinal-binding-pocket-in-sodium-ion-pump-rhodopsin
#20
Arisu Shigeta, Shota Ito, Keiichi Inoue, Takashi Okitsu, Akimori Wada, Hideki Kandori, Izuru Kawamura
The recently identified Krokinobacter rhodopsin 2 (KR2) functions as a light-driven sodium ion pump. The structure of the retinal-binding pocket of KR2 offers important in-sights into the mechanisms of KR2, which has an Asn112, Asp116, and Gln123 motif (NDQ) that is common among sodium ion pump rhodopsins, but is unique among other microbial rhodopsins. Here we present solid-state nuclear magnetic resonance (NMR) characterization of retinal and functionally important residues in the vicinity of retinal at ground state...
January 1, 2017: Biochemistry
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