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https://www.readbyqxmd.com/read/28821550/crystal-structure-of-the-tetr-family-repressor-alkx-from-dietzia-sp-dq12-45-1b-implicated-in-biodegradation-of-n-alkanes
#1
Jie-Liang Liang, Yuan Gao, Zheng He, Yong Nie, Meng Wang, Jing-Hong JiangYang, Xuejun C Zhang, Wen-Sheng Shu, Xiao-Lei Wu
n-Alkanes are ubiquitous in nature and are widely used by microorganisms as carbon sources. Alkane hydroxylation by alkane monooxygenases is a critical step in the aerobic biodegradation of n-alkanes, which plays important roles in natural alkane attenuation and is used in industrial and environmental applications. The alkane oxidation operon, alkW1-alkX, in an alkane-degrading strain Dietzia sp. DQ12-45-1b, is negatively auto-regulated by the TetR family repressor, AlkX, via a product positive feedback mechanism...
August 18, 2017: Applied and Environmental Microbiology
https://www.readbyqxmd.com/read/28818366/expression-of-recombinant-snrk1-in-e-coli-characterization-of-adenine-nucleotide-binding-to-the-snrk1-1-akin%C3%AE-%C3%AE-%C3%AE-3-complex
#2
José Luis Maya-Bernal, Alejandra Ávila, Ana Ruiz-Gayosso, Ricardo Trejo-Fregoso, Nancy Pulido, Alejandro Sosa-Peinado, Esther Zúñiga-Sánchez, Eleazar Martínez-Barajas, Rogelio Rodríguez-Sotres, Patricia Coello
The SnRK1 complexes in plants belong to the family of AMPK/SNF1 kinases, which have been associated with the control of energy balance, in addition to being involved in the regulation of other aspects of plant growth and development. Analysis of complex formation indicates that increased activity is achieved when the catalytic subunit is phosphorylated and bound to regulatory subunits. SnRK1.1 subunit activity is higher than that of SnRK1.2, which also exhibits reduced activation due to the regulatory subunits...
October 2017: Plant Science: An International Journal of Experimental Plant Biology
https://www.readbyqxmd.com/read/28813418/mechanism-of-intracellular-allosteric-%C3%AE-2ar-antagonist-revealed-by-x-ray-crystal-structure
#3
Xiangyu Liu, Seungkirl Ahn, Alem W Kahsai, Kai-Cheng Meng, Naomi R Latorraca, Biswaranjan Pani, A J Venkatakrishnan, Ali Masoudi, William I Weis, Ron O Dror, Xin Chen, Robert J Lefkowitz, Brian K Kobilka
G-protein-coupled receptors (GPCRs) pose challenges for drug discovery efforts because of the high degree of structural homology in the orthosteric pocket, particularly for GPCRs within a single subfamily, such as the nine adrenergic receptors. Allosteric ligands may bind to less-conserved regions of these receptors and therefore are more likely to be selective. Unlike orthosteric ligands, which tonically activate or inhibit signalling, allosteric ligands modulate physiologic responses to hormones and neurotransmitters, and may therefore have fewer adverse effects...
August 16, 2017: Nature
https://www.readbyqxmd.com/read/28813147/synthesis-and-evaluation-of-asymmetric-acyclic-nucleoside-bisphosphonates-as-inhibitors-of-plasmodium-falciparum-and-human-hypoxanthine-guanine-xanthine-phosphoribosyltransferase
#4
Petr Špaček, Dianne T Keough, Marina Chavchich, Martin Dracinsky, Zlatko Janeba, Lieve Naesens, Michael D Edstein, Luke W Guddat, Dana Hocková
Acyclic nucleoside bisphosphonates (ANbPs) have previously been shown to be good inhibitors of human hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and Plasmodium falciparum (Pf) hypoxanthine-guanine-xanthine phosphoribosyltransferase (PfHGXPRT). Based on this scaffold, a new series of ANbPs was synthesized. One of these new ANbPs, [3-(guanine-9-yl)-2-((2-phosphonoethoxy)methyl)propoxy]methylphosphonic acid, exhibited Ki values of 6 and 70 nM for human HGPRT and Pf HGXPRT, respectively. These low Ki values were achieved by inserting an extra carbon atom in the linker connecting the N9 atom of guanine to one of the phosphonate groups...
August 16, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28809813/molecular-mechanisms-underlying-inhibitory-binding-of-alkylimidazolium-ionic-liquids-to-laccase
#5
Jianliang Sun, Hao Liu, Wenping Yang, Shicheng Chen, Shiyu Fu
Water-miscible alkylimidazolium ionic liquids (ILs) are "green" co-solvents for laccase catalysis, but generally inhibit enzyme activity. Here, we present novel insights into inhibition mechanisms by a combination of enzyme kinetics analysis and molecular simulation. Alkylimidazolium cations competitively bound to the TI Cu active pocket in the laccase through hydrophobic interactions. Cations with shorter alkyl chains (C₂~C₆) entered the channel inside the pocket, exhibiting a high compatibility with laccase (competitive inhibition constant Kic = 3...
August 15, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28806749/defining-the-genetic-susceptibility-to-cervical-neoplasia-a-genome-wide-association-study
#6
Paul J Leo, Margaret M Madeleine, Sophia Wang, Stephen M Schwartz, Felicity Newell, Ulrika Kymmer, Kari Hemminki, Goran Hallmans, Sven Tiews, Winfried Steinberg, Janet S Rader, Felipe Castro, Mahboobeh Safaeian, Eduardo L Franco, François Coutlée, Claes Ohlsson, Adrian Cortes, Mhairi Marshall, Pamela Mukhopadhyay, Katie Cremin, Lisa G Johnson, Suzanne Garland, Sepehr N Tabrizi, Nicolas Wentzensen, Freddy Sitas, Julian Little, Maggie Cruickshank, Ian H Frazer, Allan Hildesheim, Matthew A Brown
A small percentage of women with cervical HPV infection progress to cervical neoplasia, and the risk factors determining progression are incompletely understood. We sought to define the genetic loci involved in cervical neoplasia and to assess its heritability using unbiased unrelated case/control statistical approaches. We demonstrated strong association of cervical neoplasia with risk and protective HLA haplotypes that are determined by the amino-acids carried at positions 13 and 71 in pocket 4 of HLA-DRB1 and position 156 in HLA-B...
August 14, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28806062/exploring-strategies-for-labeling-viruses-with-gold-nanoclusters-through-non-equilibrium-molecular-dynamics-simulations
#7
Emmi Pohjolainen, Sami Malola, Gerrit Groenhof, Hannu Häkkinen
Bio-compatible gold nanoclusters can be utilized as contrast agents in virus imaging. The labeling of viruses can be achieved non-covalently but site-specifically by linking the cluster to the hydrophobic pocket of a virus via a lipid-like pocket factor. We have estimated the binding affinities of three different pocket factors of echovirus 1 (EV1) in molecular dynamics simulations combined with non-equilibrium free energy calculations. We have also studied the effects on binding affinities with a pocket factor linked to the Au102pMBA44 nanocluster in different protonation states...
August 14, 2017: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/28804002/a-novel-glycoside-hydrolase-family-97-enzyme-bifunctional-%C3%AE-l-arabinopyranosidase-%C3%AE-galactosidase-from-bacteroides-thetaiotaomicron
#8
Asako Kikuchi, Masayuki Okuyama, Koji Kato, Shohei Osaki, Min Ma, Yuya Kumagai, Kana Matsunaga, Patcharapa Klahan, Takayoshi Tagami, Min Yao, Atsuo Kimura
Glycoside hydrolase family 97 (GH97) is one of the most interesting glycosidase families, which contains inverting and retaining glycosidases. Currently, only two enzyme types, α-glucoside hydrolase and α-galactosidase, are registered in the carbohydrate active enzyme database as GH97 function-known proteins. To explore new specificities, BT3661 and BT3664, which have distinct amino acid sequences when compared with that of GH97 α-glucoside hydrolase and α-galactosidase, were characterized in this study...
August 10, 2017: Biochimie
https://www.readbyqxmd.com/read/28802647/pharmacological-modulation-of-acid-sensing-ion-channels-1a-and-3-by-amiloride-and-2-guanidine-4-methylquinazoline-gmq
#9
Thomas Besson, Eric Lingueglia, Miguel Salinas
Acid-Sensing Ion Channels (ASICs) are cation channels activated by extracellular acidification that emerge as potential pharmacological targets in pain and other neurological disorders. Here, we compare the pharmacological modulation of ASIC1a and ASIC3 channels by amiloride and 2-guanidine-4-methylquinazoline (GMQ), two compounds commonly used for their in vitro and in vivo investigation. We analyzed the effect of amiloride on the pH-dependent activation and inactivation, the relative influence of the extracellular domain and the transmembrane/cytosolic domains on the effect of amiloride and GMQ using chimeras between ASIC1a and ASIC3, and how these compounds potentiate the physiologically relevant ASIC3 sustained window current...
August 9, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28802264/crystal-structure-and-substrate-specificity-modification-of-acetyl-xylan-esterase-from-aspergillus-luchuensis
#10
Dai Komiya, Akane Hori, Takuya Ishida, Kiyohiko Igarashi, Masahiro Samejima, Takuya Koseki, Shinya Fushinobu
Acetyl xylan esterase (AXE) catalyzes the hydrolysis of the acetyl bonds present in plant cell wall polysaccharides. Here, we determined the crystal structure of AXE from Aspergillus luchuensis (AlAXEA), providing the three-dimensional structure of an enzyme in the Esterase_phb family. AlAXEA shares its core α/β-hydrolase fold structure with esterases in other families, but it has an extended central β-sheet at both its ends and an extra loop. Structural comparison with a ferulic acid esterase (FAE) from Aspergillus niger indicated that AlAXEA has conserved catalytic machinery: a catalytic triad (Ser119, His259, and Asp202) and an oxyanion hole (Cys40 and Ser120)...
August 11, 2017: Applied and Environmental Microbiology
https://www.readbyqxmd.com/read/28794466/a-family-of-archaea-like-carboxylesterases-preferentially-expressed-in-the-symbiotic-phase-of-the-mychorrizal-fungus-tuber-melanosporum
#11
Davide Cavazzini, Guido Grossi, Elisabetta Levati, Francesca Vallese, Barbara Montanini, Angelo Bolchi, Giuseppe Zanotti, Simone Ottonello
An increasing number of esterases is being revealed by (meta) genomic sequencing projects, but few of them are functionally/structurally characterized, especially enzymes of fungal origin. Starting from a three-member gene family of secreted putative "lipases/esterases" preferentially expressed in the symbiotic phase of the mycorrhizal fungus Tuber melanosporum ("black truffle"), we show here that these enzymes (TmelEST1-3) are dimeric, heat-resistant carboxylesterases capable of hydrolyzing various short/medium chain p-nitrophenyl esters...
August 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28792932/structural-insights-into-ligand-recognition-by-the-lysophosphatidic-acid-receptor-lpa6
#12
Reiya Taniguchi, Asuka Inoue, Misa Sayama, Akiharu Uwamizu, Keitaro Yamashita, Kunio Hirata, Masahito Yoshida, Yoshiki Tanaka, Hideaki E Kato, Yoshiko Nakada-Nakura, Yuko Otani, Tomohiro Nishizawa, Takayuki Doi, Tomohiko Ohwada, Ryuichiro Ishitani, Junken Aoki, Osamu Nureki
Lysophosphatidic acid (LPA) is a bioactive lipid composed of a phosphate group, a glycerol backbone, and a single acyl chain that varies in length and saturation. LPA activates six class A G-protein-coupled receptors to provoke various cellular reactions. Because LPA signalling has been implicated in cancer and fibrosis, the LPA receptors are regarded as promising drug targets. The six LPA receptors are subdivided into the endothelial differentiation gene (EDG) family (LPA1-LPA3) and the phylogenetically distant non-EDG family (LPA4-LPA6)...
August 9, 2017: Nature
https://www.readbyqxmd.com/read/28792538/the-importance-of-conserved-amino-acids-in-heme-based-globin-coupled-diguanylate-cyclases
#13
Xuehua Wan, Jennifer A Saito, James S Newhouse, Shaobin Hou, Maqsudul Alam
Globin-coupled diguanylate cyclases contain globin, middle, and diguanylate cyclase domains that sense O2 to synthesize c-di-GMP and regulate bacterial motility, biofilm formation, and virulence. However, relatively few studies have extensively examined the roles of individual residues and domains of globin-coupled diguanylate cyclases, which can shed light on their signaling mechanisms and provide drug targets. Here, we report the critical residues of two globin-coupled diguanylate cyclases, EcGReg from Escherichia coli and BpeGReg from Bordetella pertussis, and show that their diguanylate cyclase activity requires an intact globin domain...
2017: PloS One
https://www.readbyqxmd.com/read/28791799/reducing-the-flexibility-of-type-ii-dehydroquinase-enzyme-for-inhibition-a-fragment-based-approach-and-molecular-dynamics-simulation-study
#14
Antonio Peón, Adrián Robles, Beatriz Blanco, Marino Convertino, Paul Thompson, Alastair R Hawkins, Amedeo Caflisch, Concepcion Gonzalez-Bello
A multidisciplinary approach was used to identify and optimize a quinazolinedione-based ligand that would reduce the flexibility of the substrate-covering loop (catalytic loop) of the type II dehydroquinase from Helicobacter pylori. This enzyme, which is essential for the survival of this bacterium, is involved in the biosynthesis of the aromatic amino acids. A computer-aided fragment-based protocol (ALTA) was first employed to identify the aromatic fragments able to block the interface pocket that separates two neighbor enzyme subunits and is located at the active site entrance...
August 9, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28777094/in-crystallo-activity-tests-with-latent-apple-tyrosinase-and-two-mutants-reveal-the-importance-of-the-mutated-sites-for-polyphenol-oxidase-activity
#15
Ioannis Kampatsikas, Aleksandar Bijelic, Matthias Pretzler, Annette Rompel
Tyrosinases are type 3 copper enzymes that belong to the polyphenol oxidase (PPO) family and are able to catalyze both the ortho-hydroxylation of monophenols and their subsequent oxidation to o-quinones, which are precursors for the biosynthesis of colouring substances such as melanin. The first plant pro-tyrosinase from Malus domestica (MdPPO1) was recombinantly expressed in its latent form (56.4 kDa) and mutated at four positions around the catalytic pocket which are believed to influence the activity of the enzyme...
August 1, 2017: Acta Crystallographica. Section F, Structural Biology Communications
https://www.readbyqxmd.com/read/28770925/global-dna-dynamics-of-8-oxoguanine-repair-by-human-ogg1-revealed-by-stopped-flow-kinetics-and-molecular-dynamics-simulation
#16
M V Lukina, V V Koval, A A Lomzov, D O Zharkov, O S Fedorova
The toxic action of different endogenous and exogenous agents leads to damage in genomic DNA. 8-Oxoguanine is one of the most often generated and highly mutagenic oxidative forms of damage in DNA. Normally, in human cells it is promptly removed by 8-oxoguanine-DNA-glycosylase hOGG1, the key DNA-repair enzyme. An association between the accumulation of oxidized guanine and an increased risk of harmful processes in organisms was already found. However, the detailed mechanism of damaged base recognition and removal is still unclear...
August 3, 2017: Molecular BioSystems
https://www.readbyqxmd.com/read/28767728/crystal-structure-of-qa-1a-with-bound-qa-1-determinant-modifier-peptide
#17
Ge Ying, Jing Wang, Vipin Kumar, Dirk M Zajonc
Qa-1 is a non-classical Major Histocompatibility (MHC) class I molecule that generally presents hydrophobic peptides including Qdm derived from the leader sequence of classical MHC I molecules for immune surveillance by NK cells. Qa-1 bound peptides derived from the TCR Vβ8.2 of activated T cells also activates CD8+ regulatory T cells to control autoimmunity and maintain self-tolerance. Four allotypes of Qa-1 (Qa-1a-d) are expressed that are highly conserved in sequence but have several variations that could affect peptide binding to Qa-1 or TCR recognition...
2017: PloS One
https://www.readbyqxmd.com/read/28766112/oleanolic-acid-and-ursolic-acid-as-potential-inhibitors-of-human-salivary-%C3%AE-amylase-insights-from-in-vitro-assays-and-in-silico-simulations
#18
Jiachen Sun, Shengjie Dong, Yueting Wu, Hui Zhao, Xia Li, Wenyuan Gao
It is known that inhibiting α-amylase, an important enzyme in digestion of starch and glycogen, is a useful strategy for treating disorders in carbohydrate uptake. Two natural components distributed in many fruits and plants, oleanolic acid and ursolic acid, are endowed with important pharmacological activities and wide therapeutic possibilities. Until now, only a tiny fraction of their applications have been identified and exploited. Our in vitro inhibition studies demonstrated that oleanolic acid and ursolic acid non-competitively inhibit the activity and function of human salivary α-amylase...
August 2017: Journal of Molecular Modeling
https://www.readbyqxmd.com/read/28766104/protein-engineering-and-homologous-expression-of-serratia-marcescens-lipase-for-efficient-synthesis-of-a-pharmaceutically-relevant-chiral-epoxyester
#19
Ke-Cai Chen, Ming-Min Zheng, Jiang Pan, Chun-Xiu Li, Jian-He Xu
The lipase isolated from Serratia marcescens (LipA) is a useful biocatalyst for kinetic resolution of a pharmaceutically relevant epoxyester, (±)-3-(4'-methoxyphenyl) glycidic acid methyl ester [(±)-MPGM], to afford optically pure (-)-MPGM, a key intermediate for the synthesis of diltiazem hydrochloride. Two mutants, LipAL315S and LipAS271F, were identified from the combinatorial saturation mutation library of 14 amino acid residues lining the substrate-binding pocket. LipAL315S, LipAS271F, and their combination LipAL315S/S271F showed 2...
August 1, 2017: Applied Biochemistry and Biotechnology
https://www.readbyqxmd.com/read/28762739/ultrafast-spectroscopic-dynamics-of-quinacrine-riboflavin-binding-protein-interactions
#20
Shiori Yamazaki, Matthew A Diaz, Thomas M Carlino, Chitra Gotluru, Mercedes Ma Mazza, Amy M Scott
Redox active cofactors play a dynamic role inside protein binding active sites because the amino acids responsible for binding participate in electron transfer (ET) reactions. Here, we use transient absorption spectroscopy to examine the ultrafast ET between quinacrine (Qc), an antimalarial drug with potential anticancer activity, and riboflavin binding protein (RfBP) with a known Kd =264 nM. Steady-state absorption reveal a ~10 nm red-shift in the ground state when QcH32+ is titrated with RfBP, and a Stern-Volmer analysis shows ~84% quenching and blue-shift of the QcH32+ photoluminescence to form a 1:1 binding ratio of the QcH3(2+)-RfBP complex...
August 1, 2017: Journal of Physical Chemistry. B
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