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https://www.readbyqxmd.com/read/28642113/paralog-divergent-features-may-help-reduce-off-target-effects-of-drugs-hints-from-glucagon-subfamily-analysis
#1
Zhining Sa, Jingqi Zhou, Yangyun Zou, Zhixi Su, Xun Gu
Side effects from targeted drugs remain a serious concern. One reason is the nonselective binding of a drug to unintended proteins such as its paralogs, which are highly homologous in sequences and have similar structures and drug-binding pockets. To identify targetable differences between paralogs, we analyzed two types (type-I and type-II) of functional divergence between two paralogs in the known target protein receptor family G-protein coupled receptors (GPCRs) at the amino acid level. Paralogous protein receptors in glucagon-like subfamily, glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R), exhibit divergence in ligands and are clinically validated drug targets for type 2 diabetes...
June 19, 2017: Genomics, Proteomics & Bioinformatics
https://www.readbyqxmd.com/read/28637865/an-evolutionarily-distinct-family-of-polysaccharide-lyases-removes-rhamnose-capping-of-complex-arabinogalactan-proteins
#2
José Munoz-Munoz, Alan Cartmell, Nicolas Terrapon, Arnaud Baslé, Bernard Henrissat, Harry J Gilbert
The human gut microbiota utilizes complex carbohydrates as major nutrients. The requirement for efficient glycan degrading systems exerts a major selective selection pressure on this microbial community. Thus, we propose that this microbial ecosystem represents a substantial resource for discovering novel carbohydrate active enzymes. To test this hypothesis we screened the potential enzymatic functions of hypothetical proteins encoded by genes of Bacteroides thetaiotaomicron that were upregulated by arabinogalactan arabinogalactan proteins or AGPs...
June 21, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28633330/the-asparagine-rich-protein-nrp-interacts-with-the-verticillium-effector-pevd1-and-regulates-the-subcellular-localization-of-cryptochrome-2
#3
Ruimin Zhou, Tong Zhu, Lei Han, Mengjie Liu, Mengyuan Xu, Yanli Liu, Dandan Han, Dewen Qiu, Qingqiu Gong, Xinqi Liu
The soil-borne fungal pathogen Verticillium dahliae infects a wide range of dicotyledonous plants including cotton, tobacco, and Arabidopsis. Among the effector proteins secreted by V. dahliae, the 16 kDa PevD1 induces a hypersensitive response in tobacco. Here we report the high-resolution structure of PevD1 with folds resembling a C2 domain-like structure with a calcium ion bound to the C-terminal acidic pocket. A yeast two-hybrid screen, designed to probe for molecular functions of PevD1, identified Arabidopsis asparagine-rich protein (NRP) as the interacting partner of PevD1...
June 13, 2017: Journal of Experimental Botany
https://www.readbyqxmd.com/read/28632393/the-antinociceptive-agent-sbfi-26-binds-to-anandamide-transporters-fabp5-and-fabp7-at-two-different-sites
#4
Hao-Chi Hsu, Simon Tong, Yuchen Zhou, Matthew W Elmes, Su Yan, Martin Kaczocha, Dale G Deutsch, Robert C Rizzo, Iwao Ojima, Huilin Li
Human FABP5 and FABP7 are intracellular endocannabinoid transporters. SBFI-26 is an -truxillic acid 1-naphthyl monoester that competitively inhibits the activities of FABP5 and FABP7 and produces antinociceptive and anti-inflammatory effects in mice. The synthesis of SBFI-26 yields several stereoisomers, and it is not known how the inhibitor binds the transporters. Here we report co-crystal structures of SBFI-26 in complex with human FABP5 and FABP7 at a resolution of 2.2 Å and 1.9 Å, respectively. We found that only (S)-SBFI-26 was present in the crystal structures...
June 20, 2017: Biochemistry
https://www.readbyqxmd.com/read/28630402/exploration-of-binding-and-inhibition-mechanism-of-a-small-molecule-inhibitor-of-influenza-virus-h1n1-hemagglutinin-by-molecular-dynamics-simulation
#5
Shanshan Guan, Tianao Wang, Ziyu Kuai, Mengdan Qian, Xiaopian Tian, Xiuqi Zhang, Yongjiao Yu, Song Wang, Hao Zhang, Hao Li, Wei Kong, Yaming Shan
Influenza viruses are a major public health threat worldwide. The influenza hemagglutinin (HA) plays an essential role in the virus life cycle. Due to the high conservation of the HA stem region, it has become an especially attractive target for inhibitors for therapeutics. In this study, molecular simulation was applied to study the mechanism of a small molecule inhibitor (MBX2329) of influenza HA. Behaviors of the small molecule under neutral and acidic conditions were investigated, and an interesting dynamic binding mechanism was found...
June 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28626565/site-specific-azide-acetyllysine-photochemistry-on-epigenetic-readers-for-interactome-profiling
#6
Babu Sudhamalla, Debasis Dey, Megan Breski, Tiffany Nguyen, Kabirul Islam
Chemical modifications on DNA, RNA and histones are recognized by an array of 'reader' modules to regulate transcriptional programming and cell fate. However, identification of reader-specific interacting partners in a dynamic cellular environment remains a significant challenge. Herein, we report a chemoproteomic approach termed 'interaction-based protein profiling' (IBPP) to characterize novel interacting partners of potentially any reader protein. IBPP harnesses a photosensitive amino acid introduced into the hydrophobic pocket of a reader module to crosslink and enrich transient interacting partners that are inaccessible to traditional methods...
June 1, 2017: Chemical Science
https://www.readbyqxmd.com/read/28625641/emergence-of-novel-and-dominant-acquired-egfr-solvent-front-mutations-at-gly796-g796s-r-together-with-c797s-r-and-l792f-h-mutations-in-one-egfr-l858r-t790m-nsclc-patient-who-progressed-on-osimertinib
#7
Sai-Hong Ignatius Ou, Jean Cui, Alexa B Schrock, Michael E Goldberg, Viola W Zhu, Lee Albacker, Philip J Stephens, Vincent A Miller, Siraj M Ali
Acquired epidermal growth factor receptor (EGFR) resistance mutations to osimertinib are common, including the EGFR C797S that abolishes the covalent binding of osimertinib to EGFR. Here we report the emergence of novel EGFR solvent front mutations at Gly796 (G796S/R) in addition to a hinge pocket L792F/H mutations, and C797S/G all in cis with T790M in a single patient on progression on osimertinib as detected by plasma circulating tumor DNA (ctDNA) assay in the course of clinical care. A 69-year-old Caucasian female former light-smoker presented with stage IV EGFR L858R positive adenocarcinoma who developed EGFR T790M mutation after 8 month treatment of erlotinib...
June 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28624736/fluorescence-of-tautomeric-forms-of-curcumin-in-different-ph-and-biosurfactant-rhamnolipids-systems-application-towards-on-off-ratiometric-fluorescence-temperature-sensing
#8
Zeinab Moussa, Mazhar Chebl, Digambara Patra
Medicinal properties of curcumin are widely getting realized. For its applicability as a hydrophobic drug molecule and food spice interaction of curcumin with rhamnolipids, a biosurfactant, bears importance. Here we have explored interaction of curcumin with rhamnolipids biosurfactant and its aggregation behavior. The impact of pH on critical micelle concentration (cmc) of rhamnolipids has been studied using fluorescence of curcumin and found that cmc of rhamnolipids increases with increase in pH of the medium...
June 11, 2017: Journal of Photochemistry and Photobiology. B, Biology
https://www.readbyqxmd.com/read/28623735/biochemical-and-structural-characterization-of-penicillium-purpurogenum-%C3%AE-d-galactosidase-binding-of-galactose-to-an-alternative-pocket-may-explain-enzyme-inhibition
#9
Luis Morales-Quintana, Carolina Faúndez, Raúl Herrera, Vasni Zavaleta, María Cristina Ravanal, Jaime Eyzaguirre, María Alejandra Moya-León
The fungus Penicillium purpurogenum degrades plant cell walls by the action of cellulolytic, xylanolytic and pectinolytic enzymes. The α-D-galactosidase is one of the enzymes which may act on pectin degradation. This enzyme has several biotechnological and medical applications. The aim of this work was to better understand the molecular mechanism of α-D-galactosidase from P. purpurogenum (GALP1). For this purpose, a gene coding for the enzyme was identified from the fungal genome and heterologously expressed in Pichia pastoris...
June 9, 2017: Carbohydrate Research
https://www.readbyqxmd.com/read/28623230/flexible-body-motions-of-calmodulin-and-the-farnesylated-hypervariable-region-yield-a-high-affinity-interaction-enabling-k-ras4b-membrane-extraction
#10
Hyunbum Jang, Avik Banerjee, Tanmay Chavan, Vadim Gaponenko, Ruth Nussinov
In calmodulin (CaM)-rich environments, oncogenic KRAS plays a critical role in adenocarcinomas by promoting PI3K/Akt signaling. We previously proposed that at elevated calcium levels in cancer, CaM recruits PI3Kα to the membrane and extracts K-Ras4B from the membrane, organizing a K-Ras4B/CaM/PI3Kα ternary complex. CaM can thereby replace a missing receptor tyrosine kinase signal to fully activate PI3Kα. Recent experimental data show that CaM selectively promotes K-Ras signaling, but not of N-Ras or H-Ras...
June 16, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28621541/expanding-the-scope-of-electrophiles-capable-of-targeting-k-ras-oncogenes
#11
Lynn M McGregor, Meredith L Jenkins, Caitlin Kerwin, John E Burke, Kevan M Shokat
There is growing interest in reversible and irreversible covalent inhibitors that target noncatalytic amino acids in target proteins. With a goal of targeting oncogenic K-Ras variants (e.g., G12D) by expanding the types of amino acids that can be targeted by covalent inhibitors, we survey a set of electrophiles for their ability to label carboxylates. We functionalized an optimized ligand for the K-Ras switch II pocket with a set of electrophiles previously reported to react with carboxylates and characterized the ability of these compounds to react with model nucleophiles and oncogenic K-Ras proteins...
June 16, 2017: Biochemistry
https://www.readbyqxmd.com/read/28620687/identification-and-characterization-of-a-biosynthetic-gene-cluster-for-tryptophan-dimers-in-deep-sea-derived-streptomyces-sp-scsio-03032
#12
Liang Ma, Wenjun Zhang, Yiguang Zhu, Guangtao Zhang, Haibo Zhang, Qingbo Zhang, Liping Zhang, Chengshan Yuan, Changsheng Zhang
Tryptophan dimers (TDs) are an important class of natural products with diverse bioactivities and share conserved biosynthetic pathways. We report the identification of a partial gene cluster (spm) responsible for the biosynthesis of a class of unusual TDs with non-planar skeletons including spiroindimicins (SPMs), indimicins (IDMs), and lynamicins (LNMs) from the deep-sea derived Streptomyces sp. SCSIO 03032. Bioinformatics analysis, targeted gene disruptions, and heterologous expression studies confirmed the involvement of the spm gene cluster in the biosynthesis of SPM/IDM/LNMs, and revealed the indispensable roles for the halogenase/reductase pair SpmHF, the amino acid oxidase SpmO, and the chromopyrrolic acid (CPA) synthase SpmD, as well as the positive regulator SpmR and the putative transporter SpmA...
June 15, 2017: Applied Microbiology and Biotechnology
https://www.readbyqxmd.com/read/28620633/efficacy-of-human-umbilical-stem-cells-cultured-on-polylactic-polyglycolic-acid-membrane-in-the-treatment-of-multiple-gingival-recession-defects-a-randomized-controlled-clinical-study
#13
Kushal Zanwar, Kiran Kumar Ganji, Manohar L Bhongade
STATEMENT OF THE PROBLEM: Recently allogenic mesenchymal stem cells are proposed to have multipotential progenitor cell capabilities to differentiate into cementoblasts, osteoblasts, and periodontal ligament fibroblasts. PURPOSE: The aim of the present study was to compare the efficacy of human umbilical stem cells cultured on polylactic acid (PLA), polyglycolic acid (PGA) membrane with PLA/PGA membrane alone in the treatment of multiple gingival recession defects...
June 2017: Journal of Dentistry
https://www.readbyqxmd.com/read/28619510/crystal-structure-of-brlr-with-c-di-gmp
#14
Harikiran Raju, Rohan Sharma
The transcriptional regulator BrlR is a member of the MerR family of multidrug transport activators in Pseudomonas aeruginosa. Recent study indicates that BrlR is a novel 3',5'-cyclic diguanylic acid (c-di-GMP) receptor and can be activated by c-di- GMP. To gain insight into BrlR function, we determined the structure of BrlR with c-di-GMP complex structure to 2.5 Å. The structure and SEC data revealed BrlR forms a tetramer and each BrlR protomer consists of three parts, DNA-binding domain, a coiled-coil region and GyrI-like domain...
June 12, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28606047/design-synthesis-and-biological-evaluation-of-vanillin-hydroxamic-acid-derivatives-as-novel-peptide-deformylase-inhibitors
#15
Jian Gao, Shengzhi Qiu, Li Liang, Zhixiang Hao, Qianqian Zhou, Fanfan Wang, Jie Mou, Qisi Lin
BACKGROUND: Infectious disease is increasingly hampering human health, which challenge the discovery of new antibacterial target. Peptide deformylase (PDF), a metalloenzyme responsible for catalyzing the remove of the N-formyl group from nascent proteins, was considered as an important target in antibacterial drug discovery. OBJECTIVE: Reported here are the design, synthesis and biological evaluation of vanillin hydroxamic acid derivatives. METHOD AND RESULTS: Analysis of the structure-activity relationships lead to the discovery of compound 8, which exhibits promising antibacterial activity against Escherichia coli, Staphylococcus aureus, Aspergillus oryzae, and Aspergillus foetidus with the MIC value of 0...
June 12, 2017: Current Computer-aided Drug Design
https://www.readbyqxmd.com/read/28605587/allosteric-regulation-of-phosphatidylinositol-4-kinase-iii-beta-by-an-anti-picornavirus-compound-mdl-860
#16
Minetaro Arita, Georgi Dobrikov, Gerhard Pürstinger, Angel Galabov
MDL-860 is a broad-spectrum anti-picornavirus compound discovered in 1982, and one of the few promising candidates effective in in vivo virus infection. Despite the effectiveness, the target and the mechanism of action of MDL-860 remain unknown. Here, we have characterized anti-poliovirus activity of MDL-860, and identified host phosphatidylinositol-4 kinase III beta (PI4KB) as the target. MDL-860 treatment caused covalent modification and irreversible inactivation of PI4KB. A cysteine residue at amino acid 646 of PI4KB, which locates at the bottom of a surface pocket apart from the active site, was identified as the target site of MDL-860...
June 12, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28603847/tight-molecular-recognition-of-benzo-a-pyrene-by-a-high-affinity-antibody
#17
Andreas Eichinger, Irmgard Neumaier, Michael Pschenitza, Reinhard Nießner, Dietmar Knopp, Arne Skerra
Benzo[a]pyrene, produced during the combustion of organic material, is an abundant noxious pollutant because of its carcinogenic metabolic degradation products. The high affinity (KD ≈ 3 nM) monoclonal antibody 22F12 allows facile bioanalytical quantification of benzo[a]pyrene even in complex matrices. Here, we report its functional and X-ray crystallographic analysis in complex with 3-hydroxybenzo[a]pyrene after cloning of the V-genes and production as a recombinant Fab fragment. The polycyclic aromatic hydrocarbon is bound in a deep pocket beween the light and heavy chains surrounded mainly by aromatic and aliphatic amino acid side chains...
June 11, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28597740/pocket-haematoma-after-cardiac-electronic-device-implantation-in-patients-receiving-antiplatelet-and-anticoagulant-treatment-a-single-centre-experience
#18
Gültekin Gunhan Demir, Gamze Babur Guler, Ekrem Guler, HacıMurat Güneş, Filiz Kizilirmak, İbrahim Oğuz Karaca, Mehmet Onur Omaygenç, Beytullah Çakal, Erkam Olgun, Umeyr Savur, Ersın Ibisoglu, Irfan Barutçu, Fethi Kiliçaslan
Objective In modern cardiology practice, implantation of cardiac electronic devices in patients taking anticoagulant or antiplatelet therapy is a common clinical scenario. Bleeding complications are of particular concern in this patient population and pocket haematoma is one of the most frequent complications. We sought to determine the relationship between periprocedural antiplatelet/anticoagulant therapy and pocket haematoma formation in patients undergoing cardiac implantable electronic device (CIED) implantation...
February 2017: Acta Cardiologica
https://www.readbyqxmd.com/read/28596102/evolution-of-the-fusogenic-activity-of-the-receptor-fgfrl1
#19
Lei Zhuang, Beat Trueb
FGFRL1 is a transmembrane receptor that can induce the fusion of CHO cells to multinucleated syncytia. This cell fusion activity has been attributed to the extracellular Ig3 domain of the receptor. We investigated how the fusogenic activity evolved during the evolution of animals. We found that the Ig3 domain from humans, mice, chicken and fish stimulates fusion of CHO cells, while the Ig3 domain from lancelet and sea urchin does not. It is therefore conceivable that the fusogenic activity of FGFRL1 developed during the evolution of vertebrates...
June 5, 2017: Archives of Biochemistry and Biophysics
https://www.readbyqxmd.com/read/28591579/sonic-hedgehog-activates-phospholipase-a2-to-enhance-smoothened-ciliary-translocation
#20
Angela M Arensdorf, Miriam E Dillard, Jacob M Menke, Matthew W Frank, Charles O Rock, Stacey K Ogden
The G protein-coupled receptor Smoothened (Smo) is the signal transducer of the Sonic Hedgehog (Shh) pathway. Smo signals through G protein-dependent and -independent routes, with G protein-independent canonical signaling to Gli effectors requiring Smo accumulation in the primary cilium. The mechanisms controlling Smo activation and trafficking are not yet clear but likely entail small-molecule binding to pockets in its extracellular cysteine-rich domain (CRD) and/or transmembrane bundle. Here, we demonstrate that the cytosolic phospholipase cPLA2α is activated through Gβγ downstream of Smo to release arachidonic acid...
June 6, 2017: Cell Reports
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