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https://www.readbyqxmd.com/read/28448128/total-chemical-synthesis-and-folding-of-all-l-and-all-d-variants-of-oncogenic-kras-g12v
#1
Adam Marc Levinson, John H McGee, Andrew G Roberts, Gardner Creech, Ting Wang, Michael T Peterson, Ronald C Hendrickson, Gregory L Verdine, Samuel J Danishefsky
The Ras proteins are essential GTPases involved in the regulation of cell proliferation and survival. Mutated oncogenic forms of Ras alter effector binding and innate GTPase activity, leading to deregulation of downstream signal transduction. Mutated forms of Ras are involved in approximately 30% of human cancers. Despite decades of effort to develop direct Ras inhibitors, Ras has long been considered 'undruggable' due to its high affinity for GTP and its lack of hydrophobic binding pockets. Herein, we report a total chemical synthesis of all-L- and all-D-amino acid biotinylated variants of oncogenic mutant KRas(G12V)...
April 27, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28446025/medicinal-plant-phytochemicals-and-their-inhibitory-activities-against-pancreatic-lipase-molecular-docking-combined-with-molecular-dynamics-simulation-approach
#2
Bilal Ahmed, Usman Ali Ashfaq, Muhammad Usman Mirza
Obesity is the worst health risk worldwide, which is linked to a number of diseases. Pancreatic lipase is considered as an affective cause of obesity and can be a major target for controlling the obesity. The present study was designed to find out best phytochemicals against pancreatic lipase through molecular docking combined with molecular dynamics (MD) simulation. For this purpose, a total of 3770 phytochemicals were docked against pancreatic lipase and ranked them on the basis of binding affinity. Finally, 10 molecules (Kushenol K, Rosmarinic acid, Reserpic acid, Munjistin, Leachianone G, Cephamycin C, Arctigenin, 3-O-acetylpadmatin, Geniposide and Obtusin) were selected that showed strong bonding with the pancreatic lipase...
April 26, 2017: Natural Product Research
https://www.readbyqxmd.com/read/28442737/structural-and-biochemical-insights-of-cypa-and-aif-interaction
#3
Biancamaria Farina, Gianluigi Di Sorbo, Angela Chambery, Andrea Caporale, Guido Leoni, Rosita Russo, Fabiola Mascanzoni, Domenico Raimondo, Roberto Fattorusso, Menotti Ruvo, Nunzianna Doti
The Cyclophilin A (CypA)/Apoptosis Inducing Factor (AIF) complex is implicated in the DNA degradation in response to various cellular stress conditions, such as oxidative stress, cerebral hypoxia-ischemia and traumatic brain injury. The pro-apoptotic form of AIF (AIF(Δ1-121)) mainly interacts with CypA through the amino acid region 370-394. The AIF(370-394) synthetic peptide inhibits complex formation in vitro by binding to CypA and exerts neuroprotection in a model of glutamate-mediated oxidative stress. Here, the binding site of AIF(Δ1-121) and AIF(370-394) on CypA has been mapped by NMR spectroscopy and biochemical studies, and a molecular model of the complex has been proposed...
April 25, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28442570/coordination-chemistry-controls-the-thiol-oxidase-activity-of-the-b12-trafficking-protein-cblc
#4
Zhu Li, Aranganathan Shanmuganathan, Markus Ruetz, Kazuhiro Yamada, Nicholas A Lesniak, Bernhard Kraeutler, Thomas C Brunold, Markos Koutmos, Ruma Banerjee
The cobalamin or B12 cofactor supports sulfur and one-carbon metabolism and the catabolism of odd-chain fatty acids, branched-chain amino acids and cholesterol. CblC is a B12 processing enzyme involved in an early cytoplasmic step in the cofactor trafficking pathway. It catalyzes the glutathione (GSH)-dependent dealkylation of alkylcobalamins and the reductive decyanation of cyanocobalamin. CblC from Caenorhabdiitis elegans (ceCblC) also exhibits a robust thiol oxidase activity converting reduced GSH to oxidized GSSG with concomitant scrubbing of ambient dissolved O2 The mechanism of thiol oxidation catalyzed by ceCblC is not known...
April 25, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28440962/designed-heme-cage-%C3%AE-sheet-miniproteins
#5
Areetha D'Souza, Xiangyang Wu, Edwin Kok Lee Yeow, Surajit Bhattacharjya
The structure and function of naturally occurring proteins are governed by a large number of amino acids (≥100). The design of miniature proteins with desired structures and functions not only substantiates our knowledge about proteins but can also contribute to the development of novel applications. Excellent progress has been made towards the design of helical proteins with diverse functions. However, the development of functional β-sheet proteins remains challenging. Herein, we describe the construction and characterization of four-stranded β-sheet miniproteins made up of about 19 amino acids that bind heme inside a hydrophobic binding pocket or "heme cage" by bis-histidine coordination in an aqueous environment...
April 25, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28439266/a-novel-regulator-of-activation-induced-cytidine-deaminase-apobecs-in-immunity-and-cancer-schr%C3%A3-dinger-s-catalytic-pocket
#6
REVIEW
Justin J King, Mani Larijani
Activation-induced cytidine deaminase (AID) and its relative APOBEC3 cytidine deaminases boost immune response by mutating immune or viral genes. Because of their genome-mutating activities, AID/APOBECs are also drivers of tumorigenesis. Due to highly charged surfaces, extensive non-specific protein-protein/nucleic acid interactions, formation of polydisperse oligomers, and general insolubility, structure elucidation of these proteins by X-ray crystallography and NMR has been challenging. Hence, almost all available AID/APOBEC structures are of mutated and/or truncated versions...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28436296/synthesis-characterization-dna-and-hsa-binding-studies-of-isomeric-pd-ii-antitumor-complexes-using-spectrophotometry-techniques
#7
Sareh Zareian-Jahromi, Hassan Mansouri-Torshizi
Two new Palladium(II) isomeric complexes, [Pd(Gly)(Leu)](I) and [Pd(Gly)(Ile)](II), where Gly is glycine, and Leu and Ile are isomeric amino acids (leucine and isoleucine), have been synthesized and characterized by elemental analysis, molar conductivity measurements, FT-IR, (1)H NMR and UV-Vis. The complexes have been tested for their In vitro cytotoxicity against cancer cell line K562 and their binding properties to calf thymus DNA (CT-DNA) and human serum albumin (HSA) have also been investigated by multispectroscopic techniques...
April 23, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28433680/organocatalyzed-and-mechanochemical-solvent-free-synthesis-of-novel-and-functionalized-bis-biphenyl-substituted-thiazolidinones-as-potent-tyrosinase-inhibitors-sar-and-molecular-modeling-studies
#8
Sadaf Mutahir, Muhammad Asim Khan, Islam Ullah Khan, Muhammad Yar, Muhammad Ashraf, Sidra Tariq, Ren-Long Ye, Bao-Jing Zhou
Eluding the involvement of solvents in organic synthesis and introducing environment friendly procedures can control environmental problems. A facile and an efficient solvent free mechanochemical method (grinding) is achieved to synthesize novel bis-biphenyl substituted thiazolidinones using non-toxic and cheap N-acetyl glycine (NAG). Organocatalytic condensation of a series of Schiff's bases bearing different substituents with thioglycolic acid produces a variety of thiazolidinones derivatives in good to excellent yield...
April 13, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28433539/rationally-designed-pi3k%C3%AE-mutants-to-mimic-atr-and-their-use-to-understand-binding-specificity-of-atr-inhibitors
#9
Yipin Lu, Mark Knapp, Kenneth Crawford, Robert Warne, Robert Elling, Kelly Yan, Michael Doyle, Gwynn Pardee, Li Zhang, Sylvia Ma, Mulugeta Mamo, Elizabeth Ornelas, Yue Pan, Dirksen Bussiere, Johanna Jansen, Isabel Zaror, Albert Lai, Paul Barsanti, Janet Sim
ATR, a protein kinase in the PIKK family, plays a critical role in the cell DNA-damage response and is an attractive anticancer drug target. Several potent and selective inhibitors of ATR have been reported showing significant antitumor efficacy, with most advanced ones entering clinical trials. However, due to the absence of an experimental ATR structure, the determinants contributing to ATR inhibitors' potency and specificity are not well understood. Here we present the mutations in the ATP-binding site of PI3Kα to progressively transform the pocket to mimic that of ATR...
April 19, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28432776/exploring-non-obvious-hydrophobic-binding-pockets-on-protein-surfaces-increasing-affinities-in-peptide-protein-interactions
#10
Lars Baltzer, Aleksandra Balliu
A 42-residue polypeptide conjugated to a small organic molecule capable of targeting the phosphorylated side chain of Ser-15 was shown to bind glycogen phosphorylase a (GPa) with a KD of 280 nM. The replacement of hydrophobic amino acids by Ala reduced affinities, whereas the incorporation of L-2-aminooctanoic acid (Aoc) increased affinities. Replacing Nle-5, Ile-9 and Leu-12 by Aoc reduced the KD from 280 nM to 27 nM. Downsizing the 42-mer to an 11-mer gave rise to an order of magnitude lower affinity for GPa but the 11-mer where Nle-5, Ile-9 and Leu-12 were replaced by Aoc showed a KD of 550 nM, comparable to that of the parent 42-mer...
April 22, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28417359/an-improved-kinetic-assay-for-the-characterization-of-metal-dependent-pectate-lyases
#11
Darryl R Jones, Richard McLean, D Wade Abbott
Pectate lyases are a subset of polysaccharide lyases (PLs) that specifically utilize a metal dependent β-elimination mechanism to cleave glyosidic bonds in homogalacturonan (HG; α-D-1,4-galacturonic acid). Most commonly, PLs harness calcium for catalysis; however, some PL families (e.g., PL2 and PL22) display preferences for transitional metals. Deploying alternative metals during β-elimination is correlated with signature coordination pocket chemistry, and is reflective of the evolution, functional specialization, and cellular location of PL activity...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28417169/rational-design-of-substrate-binding-pockets-in-polyphosphate-kinase-for-use-in-cost-effective-atp-dependent-cascade-reactions
#12
Hao Cao, Kaili Nie, Chengcheng Li, Haijun Xu, Fang Wang, Tianwei Tan, Luo Liu
Adenosine-5'-triphosphate (ATP) is the energy equivalent of the living system. Polyphosphate (polyP) is the ancient energy storage equivalent of organisms. Polyphosphate kinases (PPKs) catalyze the polyP formation or ATP formation, to store energy or to regenerate ATP, respectively. However, most PPKs are active only in the presence of long polyPs, which are more difficult and more expensive to generate than the short polyPs. We investigated the PPK preference towards polyPs by site-directed mutagenesis and computational simulation, to understand the mechanism and further design enzymes for effective ATP regeneration using short polyPs for in vitro cascade reactions, which are highly desired for research and applications...
April 18, 2017: Applied Microbiology and Biotechnology
https://www.readbyqxmd.com/read/28412768/assessing-the-dispersive-and-electrostatic-components-of-the-selenium-aromatic-interaction-energy-by-dft
#13
Milan Senćanski, Ivana Djordjević, Sonja Grubišić
Selenium has been increasingly recognized as an important element in biological systems, which participates in numerous biochemical processes in organisms, notably in enzyme reactions. Selenium can substitute sulfur of cysteine and methionine to form their selenium analogues, selenocysteine (Sec) and selenomethionine (SeM). The nature of amino acid pockets in proteins is dependent on their composition and thus different non-covalent forces determine the interactions between selenium of Sec or SeM and other functional groups, resulting in specific biophysical behavior...
May 2017: Journal of Molecular Modeling
https://www.readbyqxmd.com/read/28405665/expanding-the-substrate-scope-of-phenylalanine-ammonia-lyase-from-petroselinum-crispum-towards-styrylalanines
#14
László Csaba Bencze, Alina Filip, Gergely Bánóczi, Monica Ioana Toşa, Florin Dan Irimie, Ákos Gellért, László Poppe, Csaba Paizs
This study focuses on the expansion of the substrate scope of phenylalanine ammonia-lyase from Petroselinum crispum (PcPAL) towards the l-enantiomers of racemic styrylalanines rac-1a-d - which are less studied and synthetically challenging unnatural amino acids - by reshaping the aromatic binding pocket of the active site of PcPAL by point mutations. Ammonia elimination from l-styrylalanine (l-1a) catalyzed by non-mutated PcPAL (wt-PcPAL) took place with a 777-fold lower kcat/KM value than the deamination of the natural substrate, l-Phe...
April 13, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28401569/influences-on-viral-replication-and-sensitivity-to-gls4-a-hap-compound-of-naturally-occurring-t109-v124-mutations-in-hepatitis-b-virus-core-protein
#15
Jianghua Wang, Haiying Zhang, Yingjun Zhang, Dong Jiang, Jing Li, Siegfried Goldmann, Qingyun Ren, Ran Fei, Xueyan Wang, Lai Wei
Heteroaryldihydropyrimidine (HAP) compounds inhibit HBV replication by binding to a hydrophobic pocket at the interface between hepatitis B virus core protein (HBcAg) dimer, which interrupts capsid assembly by changing the kinetics and thermodynamics during this process. Structure biological studies have identified several amino acids in HBcAg crucial for compound binding. Here we investigated the polymorphisms of T109 and V124 amino acids in HBV sequences submitted to GenBank database. Naturally occurring T109 and V124 and/or possible compensatory mutations in neighbored amino acids were introduced into HBV-expressing plasmids...
April 12, 2017: Journal of Medical Virology
https://www.readbyqxmd.com/read/28399673/pharmacophore-generation-atom-based-3d-qsar-and-molecular-dynamics-simulation-analyses-of-pyridine-3-carboxamide-6-yl-urea-analogues-as-potential-gyrase-b-inhibitors
#16
M A Azam, J Thathan
DNA gyrase subunit B (GyrB) is an attractive drug target for the development of antibacterial agents with therapeutic potential. In the present study, computational studies based on pharmacophore modelling, atom-based QSAR, molecular docking, free binding energy calculation and dynamics simulation were performed on a series of pyridine-3-carboxamide-6-yl-urea derivatives. A pharmacophore model using 49 molecules revealed structural and chemical features necessary for these molecules to inhibit GyrB. The best fitted model AADDR...
April 12, 2017: SAR and QSAR in Environmental Research
https://www.readbyqxmd.com/read/28392261/bound-waters-mediate-binding-of-diverse-substrates-to-a-ubiquitin-ligase
#17
Juliana Muñoz-Escobar, Edna Matta-Camacho, Cordelia Cho, Guennadi Kozlov, Kalle Gehring
The N-end rule pathway controls the half-life of proteins based on their N-terminal residue. Positively charged type 1 N-degrons are recognized by a negatively charged pocket on the Zn finger named the UBR box. Here, we show that the UBR box is rigid, but bound water molecules in the pocket provide the structural plasticity required to bind different positively charged amino acids. Ultra-high-resolution crystal structures of arginine, histidine, and methylated arginine reveal that water molecules mediate the binding of N-degron peptides...
March 27, 2017: Structure
https://www.readbyqxmd.com/read/28389542/characterization-of-five-fatty-aldehyde-dehydrogenase-enzymes-from-marinobacter-and-acinetobacter-structural-insights-into-the-aldehyde-binding-pocket
#18
Jonathan H Bertram, Kalene M Mulliner, Ke Shi, Mary H Plunkett, Peter Nixon, Nicholas A Serratore, Christopher J Douglas, Hideki Aihara, Brett M Barney
Enzymes involved in lipid biosynthesis and metabolism play an important role in energy conversion and storage, and in the function of structural components such as cell membranes. The fatty aldehyde dehydrogenase (FAldDH) plays a central function in the metabolism of lipid intermediates, oxidizing fatty aldehydes to the corresponding fatty acid, and competing with pathways that would further reduce the fatty aldehydes to fatty alcohols or require the fatty aldehydes to produce alkanes. In this report, the genes for four putative FAldDH enzymes from Marinobacter aquaeolei VT8 and an additional enzyme from Acinetobacter baylyi were heterologously expressed in Escherichia coli and shown to display FAldDH activity...
April 7, 2017: Applied and Environmental Microbiology
https://www.readbyqxmd.com/read/28385652/hmus-from-yersinia-pseudotuberculosis-is-a-non-canonical-heme-degrading-enzyme-to-acquire-iron-from-heme
#19
Masato Onzuka, Yukari Sekine, Takeshi Uchida, Koichiro Ishimori, Shin-Ichi Ozaki
Some Gram-negative pathogens import host heme into the cytoplasm and utilize it as an iron source for their survival. We report here that HmuS, encoded by the heme utilizing system (hmu) locus, cleaves the protoporphyrin ring to release iron from heme. A liquid chromatography/mass spectrometry analysis revealed that the degradation products of this reaction are two biliverdin isomers that result from transformation of a verdoheme intermediate. This oxidative heme degradation by HmuS required molecular oxygen and electrons supplied by either ascorbate or NADPH...
April 3, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28384393/d-cysteine-ligands-control-metal-geometries-within-de-novo-designed-three-stranded-coiled-coils
#20
Vincent Louis Pecoraro, Leela Ruckthong, Anna F A Peacock, Cherilyn E Pascoe, Lars Hemmingsen, Jeanne A Stuckey
While metal ion binding to naturally occurring L-amino acid proteins is well documented, understanding the impact of the opposite chirality (D) amino acids on the structure and stereochemistry of metals is in its infancy. We examine the effect of a D-configuration cysteine within a designed L-amino acid three-stranded coiled coil in order to enforce a precise coordination number on a metal center. The D-chirality does not alter the native fold, but the side-chain reorientation modifies the sterics of the metal binding pocket...
April 6, 2017: Chemistry: a European Journal
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