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https://www.readbyqxmd.com/read/28541290/tailoring-nanoscopic-confines-to-maximize-catalytic-activity-of-hydronium-ions
#1
Hui Shi, Sebastian Eckstein, Aleksei Vjunov, Donald M Camaioni, Johannes A Lercher
Acid catalysis by hydronium ions is ubiquitous in aqueous-phase organic reactions. Here we show that hydronium ion catalysis, exemplified by intramolecular dehydration of cyclohexanol, is markedly influenced by steric constraints, yielding turnover rates that increase by up to two orders of magnitude in tight confines relative to an aqueous solution of a Brønsted acid. The higher activities in zeolites BEA and FAU than in water are caused by more positive activation entropies that more than offset higher activation enthalpies...
May 25, 2017: Nature Communications
https://www.readbyqxmd.com/read/28539218/switching-subtype-selectivity-fragment-replacement-strategy-affords-novel-class-of-peroxisome-proliferator-activated-receptor-%C3%AE-%C3%AE-ppar%C3%AE-%C3%AE-dual-agonists
#2
Ryuta Shioi, Shogo Okazaki, Tomomi Noguchi-Yachide, Minoru Ishikawa, Makoto Makishima, Yuichi Hashimoto, Takao Yamaguchi
Peroxisome proliferator-activated receptors (PPARs) are important drug targets for treatment of dyslipidemia, type 2 diabetes, cardiovascular disease, nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, and great efforts have been made to develop novel PPAR ligands. However, most existing PPAR ligands contain a carboxylic acid (CA) or thiazolidinedione (TZD) structure (acidic head group) that is essential for activity. We recently discovered non-CA/TZD class PPARα/δ partial agonists, which contain an acetamide moiety and adjacent methyl group, linked to a 1,2,4-oxadiazole ring ("fragment a")...
May 13, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28537923/aldehyde-dehydrogenase-1a1-increases-nadh-levels-and-promotes-tumor-growth-via-glutathione-dihydrolipoic-acid-dependent-nad-reduction
#3
Baiyun Wang, Xue Chen, Zixi Wang, Wei Xiong, Tao Xu, Xinyuan Zhao, Yang Cao, Yanru Guo, Lin Li, She Chen, Song Huang, Xiaodong Wang, Min Fang, Zhirong Shen
Aldehyde dehydrogenase 1A1 (ALDH1A1) is a member of the aldehyde dehydrogenase superfamily that oxidizes aldehydes to their corresponding acids, reactions that are coupled to the reduction of NAD+ to NADH. We report here that ALDH1A1 can also use glutathione (GSH) and dihydrolipoic acid (DHLA) as electron donors to reduce NAD+ to NADH. The GSH/DHLA-dependent NAD+-reduction activity of ALDH1A1 is not affected by the aldehyde dehydrogenase inhibitor or by mutation of the residues in its aldehyde-binding pocket...
May 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28534491/structural-basis-for-perception-of-diverse-chemical-substances-by-t1r-taste-receptors
#4
Nipawan Nuemket, Norihisa Yasui, Yuko Kusakabe, Yukiyo Nomura, Nanako Atsumi, Shuji Akiyama, Eriko Nango, Yukinari Kato, Mika K Kaneko, Junichi Takagi, Maiko Hosotani, Atsuko Yamashita
The taste receptor type 1 (T1r) family perceives 'palatable' tastes. These receptors function as T1r2-T1r3 and T1r1-T1r3 heterodimers to recognize a wide array of sweet and umami (savory) tastes in sugars and amino acids. Nonetheless, it is unclear how diverse tastes are recognized by so few receptors. Here we present crystal structures of the extracellular ligand-binding domains (LBDs), the taste recognition regions of the fish T1r2-T1r3 heterodimer, bound to different amino acids. The ligand-binding pocket in T1r2LBD is rich in aromatic residues, spacious and accommodates hydrated percepts...
May 23, 2017: Nature Communications
https://www.readbyqxmd.com/read/28533982/lid-opening-and-conformational-stability-of-t1-lipase-is-mediated-by-increasing-chain-length-polar-solvents
#5
Jonathan Maiangwa, Mohd Shukuri Mohamad Ali, Abu Bakar Salleh, Raja Noor Zaliha Raja Abd Rahman, Yahaya M Normi, Fairolniza Mohd Shariff, Thean Chor Leow
The dynamics and conformational landscape of proteins in organic solvents are events of potential interest in nonaqueous process catalysis. Conformational changes, folding transitions, and stability often correspond to structural rearrangements that alter contacts between solvent molecules and amino acid residues. However, in nonaqueous enzymology, organic solvents limit stability and further application of proteins. In the present study, molecular dynamics (MD) of a thermostable Geobacillus zalihae T1 lipase was performed in different chain length polar organic solvents (methanol, ethanol, propanol, butanol, and pentanol) and water mixture systems to a concentration of 50%...
2017: PeerJ
https://www.readbyqxmd.com/read/28531287/bacterial-rna-polymerase-caps-rna-with-various-cofactors-and-cell-wall-precursors
#6
Christina Julius, Yulia Yuzenkova
Bacterial RNA polymerase is able to initiate transcription with adenosine-containing cofactor NAD+, which was proposed to result in a portion of cellular RNAs being 'capped' at the 5΄ end with NAD+, reminiscent of eukaryotic cap. Here we show that, apart from NAD+, another adenosine-containing cofactor FAD and highly abundant uridine-containing cell wall precursors, UDP-Glucose and UDP-N-acetylglucosamine are efficiently used to initiate transcription in vitro. We show that the affinity to NAD+ and UDP-containing factors during initiation is much lower than their cellular concentrations, and that initiation with them stimulates promoter escape...
May 22, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28528697/an-embryonic-stem-cell-specific-nurd-complex-functions-through-interaction-with-wdr5
#7
Ly-Sha Ee, Kurtis N McCannell, Yang Tang, Nancy Fernandes, W Rod Hardy, Michael R Green, Feixia Chu, Thomas G Fazzio
The Nucleosome Remodeling and Deacetylase (NuRD) complex is a chromatin regulatory complex that functions as a transcriptional co-repressor in metazoans. The NuRD subunit MBD3 is essential for targeting and assembly of a functional NuRD complex as well as embryonic stem cell (ESC) pluripotency. Three MBD3 isoforms (MBD3A, MBD3B, and MBD3C) are expressed in mouse. Here, we find that the MBD3C isoform contains a unique 50-amino-acid N-terminal region that is necessary for MBD3C to specifically interact with the histone H3 binding protein WDR5...
May 17, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28523927/retinoid-bms411-4-5-5-dimethyl-8-phenyl-5-6-dihydronaphthalen-2-yl-carbonyl-amino-benzoic-acid-a-potential-inhibitor-of-ns5a-protein-of-hepatitis-c-virus-a-candidate-for-combined-therapy-of-hepatitis-c-infection
#8
S Ibrahim, M J Asad, R T Mahmood, F H Wattoo, S Akhter, D Shahwar
Hepatitis C infection is a serious health issue worldwide caused by hepatitis C virus (HCV). There is an urgent need of search for new direct acting antiviral drugs due to the rapid development of drug resistance. The HCV NS5A protein is involved in creating resistance against antiviral therapy and there are also many reports that vitamin A deficiency is associated with non-responsiveness to antiviral treatment in HCV infected patients. So the present in silico study was aimed to find the relation between vitamin A deficiency and the NS5A protein's function in antiviral resistance...
2017: Acta Virologica
https://www.readbyqxmd.com/read/28522264/discovery-synthesis-and-structure-activity-relations-of-3-4-dihydro-1h-spiro-naphthalene-2-2-piperidin-1-ones-as-potassium-competitive-acid-blockers
#9
Toshihiro Imaeda, Koji Ono, Kazuo Nakai, Yasunobu Hori, Jun Matsukawa, Terufumi Takagi, Yasushi Fujioka, Naoki Tarui, Mitsuyo Kondo, Akio Imanishi, Nobuhiro Inatomi, Masahiro Kajino, Fumio Itoh, Haruyuki Nishida
With the aim to discover a gastric antisecretory agent more potent than the existing proton pump inhibitors, novel 3,4-dihydro-1H-spiro(naphthalene-2,2'-piperidin)-1-one derivatives, which could occupy two important lipophilic pockets (described as LP-1 and LP-2) of H(+),K(+)-ATPase and can strongly bind to the K(+)-binding site, were designed based on a docking model. Among the compounds synthesized, compound 4d showed a strong H(+),K(+)-ATPase-inhibitory activity and a high stomach concentration in rats, resulting in potent inhibitory action on histamine-stimulated gastric acid secretion in rats...
May 6, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28517974/the-impact-of-docosahexaenoic-acid-therapy-on-subgingival-plaque-microbiota
#10
Asghar Z Naqvi, Lin Mu, Hatice Hasturk, Thomas E Van Dyke, Kenneth J Mukamal, J Max Goodson
OBJECTIVE: The aim of this study was to evaluate the impact of docosahexaenoic acid (DHA) with low-dose aspirin therapy on periodontal bacterial profile in patients with periodontitis. BACKGROUND: We recently showed that oral DHA + aspirin therapy reduces periodontal pocket depth and local inflammatory mediators in gingival crevicular fluid (GCF) among patients with untreated chronic periodontal disease. Whether or not DHA + aspirin therapy influences specific bacterial burden in this setting is unknown...
May 18, 2017: Journal of Periodontology
https://www.readbyqxmd.com/read/28510056/the-two-sides-of-a-lipid-protein-story
#11
REVIEW
Luis G Mansor Basso, Luis F Santos Mendes, Antonio J Costa-Filho
Protein-membrane interactions play essential roles in a variety of cell functions such as signaling, membrane trafficking, and transport. Membrane-recruited cytosolic proteins that interact transiently and interfacially with lipid bilayers perform several of those functions. Experimental techniques capable of probing changes on the structural dynamics of this weak association are surprisingly limited. Among such techniques, electron spin resonance (ESR) has the enormous advantage of providing valuable local information from both membrane and protein perspectives by using intrinsic paramagnetic probes in metalloproteins or by attaching nitroxide spin labels to proteins and lipids...
June 2016: Biophysical Reviews
https://www.readbyqxmd.com/read/28509930/elucidation-of-inhibitor-binding-pockets-of-d-amino-acid-oxidase-using-docking-simulation-and-n-sulfanylethylanilide-based-labeling-technology
#12
Taiki Kohiki, Yusuke Kato, Yusuke Nishikawa, Kazuko Yorita, Ikuko Sagawa, Masaya Denda, Tsubasa Inokuma, Akira Shigenaga, Kiyoshi Fukui, Akira Otaka
Because of the relevance of d-serine (d-Ser) to schizophrenia, inhibitors of d-amino acid oxidase (DAO), which catalyzes degradation of d-Ser in the presence of flavin adenine dinucleotide (FAD), are expected to be anti-schizophrenia therapeutics. In this study, binding pockets of DAO to its inhibitor 4-bromo-3-nitrobenzoic acid were searched by combining in silico docking simulation and labeling experiments employing an N-sulfanylethylanilide-based labeling technology that we have developed. The results clearly demonstrated that there are two binding pockets: one is shared with d-Ser and FAD, and the other is an unexpected cleft between the subunits of a DAO dimer...
May 16, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28507719/broad-substrate-tolerance-of-tubulin-tyrosine-ligase-enables-one-step-site-specific-enzymatic-protein-labeling
#13
Dominik Schumacher, Oliver Lemke, Jonas Helma, Lena Gerszonowicz, Verena Waller, Tina Stoschek, Patrick M Durkin, Nediljko Budisa, Heinrich Leonhardt, Bettina G Keller, Christian P R Hackenberger
The broad substrate tolerance of tubulin tyrosine ligase is the basic rationale behind its wide applicability for chemoenzymatic protein functionalization. In this context, we report that the wild-type enzyme enables ligation of various unnatural amino acids that are substantially bigger than and structurally unrelated to the natural substrate, tyrosine, without the need for extensive protein engineering. This unusual substrate flexibility is due to the fact that the enzyme's catalytic pocket forms an extended cavity during ligation, as confirmed by docking experiments and all-atom molecular dynamics simulations...
May 1, 2017: Chemical Science
https://www.readbyqxmd.com/read/28505536/design-synthesis-molecular-docking-and-cytotoxic-evaluation-of-novel-2-furybenzimidazoles-as-vegfr-2-inhibitors
#14
Mona A Abdullaziz, Heba T Abdel-Mohsen, Ahmed M El Kerdawy, Fatma A F Ragab, Mamdouh M Ali, Sherifa M Abu-Bakr, Adel S Girgis, Hoda I El Diwani
Inhibition of angiogenesis through inhibition of vascular endothelial growth factor receptor 2 (VEGFR-2) has been applied in cancer therapy because of its important role in promoting cancer growth and metastasis. In the presented study, a series of benzimidazol-furan hybrids was designed and synthesized through facile synthetic pathways. Evaluation of the synthesized compounds for their in vitro cytotoxic activity against breast (MCF-7) and hepatocellular (HepG2) carcinoma cell lines was performed. Two of the synthesized conjugates, 10b and 15, showed potent antiproliferative properties against MCF-7 cell line (IC50 = 21...
April 26, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28501212/a-selective-and-sensitive-fluorescent-probe-for-the-determination-of-hsa-and-trypsin
#15
Shanshan Huang, Fangfang Li, Caiyun Liao, Baozhan Zheng, Juan Du, Dan Xiao
A simple fluorescent probe HBI-GR based on the combination of the fluorophore (p-HBI) in green fluorescent protein (GFP) and Guanine riboside (GR) for HSA was successfully synthesized. HBI-GR showed an obvious fluorescence enhancement toward HSA without interference from other proteins, amino acids, anions and commonly existing metal ions. HBI-GR exhibited high sensitivity towards HSA with a good linear relationship between the fluorescence intensity of HBI-GR and HSA concentration from 0 to 0.06mgmL(-1). The limit of detection, based on a signal-to-noise ratio of 3, was 15...
August 1, 2017: Talanta
https://www.readbyqxmd.com/read/28500346/structural-studies-of-the-periplasmic-portion-of-the-diguanylate-cyclase-cdgh-from-vibrio-cholerae
#16
Min Xu, Yi-Zhi Wang, Xiu-An Yang, Tao Jiang, Wei Xie
Cyclic diguanylate monophosphate (c-di-GMP) is a second messenger involved in bacterial signal transduction and produced by diguanylate cyclases (DGCs) generally containing highly variable periplasmic signal-recognition domains. CdgH is a DGC enzyme that regulates rugosity associated phenotypes in Vibrio cholerae. CdgH has two N-terminal tandem periplasmic substrate-binding (PBPb) domains for its signal recognition; however, the role of the tandem PBPb domains remains unclear. Here, we reported the crystal structure of the periplasmic portion of CdgH, which indicated that both tandem PBPb domains consist of typical interlobe ligand-binding architecture...
May 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28488219/inhibition-of-gelatinases-mmp-2-and-mmp-9-by-withania-somnifera-phytochemicals-confers-neuroprotection-in-stroke-an-in-silico-analysis
#17
Gaurav Kumar, Ranjana Patnaik
A stroke or cerebrovascular accident is a serious, life-threatening medical condition that occurs when the blood supply to part of the brain is severely reduced or cut off, depriving brain tissue of oxygen and nutrients. Studies suggested that level of gelatinases (MMP-2 and MMP-9) usually increases in the brain after stroke. The elevated activity of gelatinases plays the deleterious role in ischemic stroke, hemorrhagic stroke and perinatal hypoxic-ischemic brain injury. Therefore, matrix metalloproteinase (MMP)-2 and MMP-9 inhibition have therapeutic importance in stroke condition...
May 9, 2017: Interdisciplinary Sciences, Computational Life Sciences
https://www.readbyqxmd.com/read/28487427/structural-basis-for-linezolid-binding-site-rearrangement-in-the-staphylococcus-aureus-ribosome
#18
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/28479293/crystal-structure-and-biological-implications-of-a-glycoside-hydrolase-family-55-%C3%AE-1-3-glucanase-from-chaetomium-thermophilum
#19
Anastassios C Papageorgiou, Jinyin Chen, Duochuan Li
Crystal structures of a β-1,3-glucanase from the thermophilic fungus Chaetomium thermophilum were determined at 1.20 and 1.42Å resolution in the free and glucose-bound form, respectively. This is the third structure of a family 55 glycoside hydrolase (GH55) member and the second from a fungus. Based on comparative structural studies and site-directed mutagenesis, Glu654 is proposed as the catalytic acid residue. The substrate binding cleft exhibits restricted access on one side, rendering the enzyme as an exo-β-1,3-glucanase as confirmed also by thin layer chromatography experiments...
May 4, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28475686/quercitrin-and-quercetin-3-%C3%AE-d-glucoside-as-chemical-chaperones-for-the-a4v-sod1-als-causing-mutant
#20
Philbert Ip, Priya Roy Sharda, Anna Cunningham, Sumon Chakrabartty, Vijay Pande, Avijit Chakrabartty
In many cases of familial amyotrophic lateral sclerosis (ALS), mutant forms of the Cu,Zn superoxide dismutase protein (SOD1) misfold and aggregate in motor neurons. Monomers of the normally homodimeric SOD1 have been found in patient tissue, presymptomatic mouse models of ALS, and in vitro misfolding assays which suggests that monomerization might be an early step in the pathological SOD1 misfolding pathway. In this study, we targeted the dimer interface with small molecules that might act as chemical chaperones to stabilize the native dimer and prevent downstream misfolding and aggregation...
May 5, 2017: Protein Engineering, Design & Selection: PEDS
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