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acid pocket

Luis Schiper, Bluma Linkowski Faintuch, Roberto José da Silva Badaró, Erica Aparecida de Oliveira, Victor E Arana Chavez, Elisangela Chinen, Joel Faintuch
OBJECTIVES: Conventional imaging methods are excellent for the morphological characterization of the consequences of osteonecrosis; however, only specialized techniques have been considered useful for obtaining functional information. To explore the affinity of radiotracers for severely devascularized bone, a new mouse model of isolated femur implanted in a subcutaneous abdominal pocket was devised. To maintain animal mobility and longevity, the femur was harvested from syngeneic donors...
October 1, 2016: Clinics
Raphael Gasper, Isabelle Effenberger, Piotr Kolesinski, Barbara Terlecka, Eckhard Hofmann, Andreas Schaller
Dirigent proteins impart stereoselectivity to phenoxy radical coupling reactions in plants and thus play an essential role in the biosynthesis of biologically active natural products. This includes the regio- and enantioselective coupling and subsequent cyclization of two coniferyl alcohol radicals to pinoresinol as the committed step of lignan biosynthesis. The reaction is controlled by dirigent proteins which, depending on the species and protein, direct the reaction to either (+)- or (-)-pinoresinol. We present the crystal structure of the (-)-pinoresinol forming Dirigent Protein 6 from Arabidopsis thaliana (AtDIR6) with data to 1...
October 17, 2016: Plant Physiology
Fan Meng, Hao Yang, Colin Jack, Huaqun Zhang, Abraham Moller, Devin Spivey, Richard C Page, David L Tierney, Michael W Crowder
Matrix metalloproteinase 7 (MMP7/matrilysin-1) has been implicated in many pathological conditions, such as in cancer and inflammatory diseases; therefore, MMP7 has been targeted for drugs. Success in developing a clinical inhibitor, which exhibits suitable specificity and selectivity, will likely require structural and/or kinetic evaluation of enzyme/inhibitor interactions. To enable these future studies we herein describe the over-expression, purification, and characterization of the catalytic domain of MMP7 (cdMMP7)...
October 14, 2016: Journal of Inorganic Biochemistry
Anahita Nourmahnad, Alex T Stern, Mayo Hotta, Deirdre S Stewart, Alexis M Ziemba, Andrea Szabo, Stuart A Forman
BACKGROUND: γ-Aminobutyric acid type A (GABAA) receptors mediate important effects of intravenous general anesthetics. Photolabel derivatives of etomidate, propofol, barbiturates, and a neurosteroid get incorporated in GABAA receptor transmembrane helices M1 and M3 adjacent to intersubunit pockets. However, photolabels have not been consistently targeted at heteromeric αβγ receptors and do not form adducts with all contact residues. Complementary approaches may further define anesthetic sites in typical GABAA receptors...
October 7, 2016: Anesthesiology
Marat R Talipov, Jaladhi Nayak, Michael Lepley, Robert D Bongard, Daniel S Sem, Ramani Ramchandran, Rajendra Rathore
DUSP5 is an inducible nuclear dual-specificity phosphatase that specifically interacts with and deactivates extracellular signal-regulated kinases ERK1 and ERK2, which are responsible for cell proliferation, differentiation, and survival. The phosphatase domain (PD) of DUSP5 has unique structural features absent in other nuclear DUSPs, such as presence of a secondary anion-binding site in the proximity to the reaction center and a glutamic acid E264 positioned next to the catalytic cysteine C263, as well as a remote intra-molecular disulfide linkage...
October 14, 2016: Biochemistry
Nedyalka Radeva, Johannes Schiebel, Xiaojie Wang, Stefan G Krimmer, Kan Fu, Martin Stieler, Frederik R Ehrmann, Alexander Metz, Thomas Rickmeyer, Michael Betz, Johan Winquist, Ah Young Park, Franziska U Huschmann, Manfred S Weiss, Uwe Mueller, Andreas Heine, Gerhard Klebe
Crystallography is frequently used as follow-up method to validate hits identified by biophysical screening cascades. The capacity of crystallography to directly screen fragment libraries is often underestimated, due to its supposed low-throughput and need for high-quality crystals. We applied crystallographic fragment screening to map the protein-binding site of the aspartic protease endothiapepsin by individual soaking experiments. Here, we report on 41 fragments binding to the catalytic dyad and adjacent specificity pockets...
October 11, 2016: Journal of Medicinal Chemistry
David B Guiliano, Helen North, Eleni Panayoitou, Elaine C Campbell, Kirsty McHugh, Fiona G M Cooke, Marine Silvestre, Paul Bowness, Simon J Powis, Antony N Antoniou
Objective - HLA-B27 is associated with the inflammatory spondyloarthropathies (SpAs). Of significance, subtypes HLA-B*27:06 and HLA-B*27:09 are not associated with the SpAs. These subtypes primarily differ from the HLA-B*27:05 disease associated allele at residues 114 and 116 of the heavy chain, part of the F pocket of the antigen-binding groove. Dimerisation of HLA-B27 during assembly has been implicated in disease onset. This study investigated the factors influencing differences in dimerisation between disease associated and non-associated HLA-B27 alleles...
October 9, 2016: Arthritis & Rheumatology
Sara L Morales-Lázaro, Itzel Llorente, Félix Sierra-Ramírez, Ana E López-Romero, Miguel Ortíz-Rentería, Barbara Serrano-Flores, Sidney A Simon, León D Islas, Tamara Rosenbaum
The transient receptor potential vanilloid 1 (TRPV1) ion channel is mainly found in primary nociceptive afferents whose activity has been linked to pathophysiological conditions including pain, itch and inflammation. Consequently, it is important to identify naturally occurring antagonists of this channel. Here we show that a naturally occurring monounsaturated fatty acid, oleic acid, inhibits TRPV1 activity, and also pain and itch responses in mice by interacting with the vanilloid (capsaicin)-binding pocket and promoting the stabilization of a closed state conformation...
October 10, 2016: Nature Communications
Ishfaq A Sheikh, Muhammad Yasir, Muhammad Abu-Elmagd, Tanveer A Dar, Adel M Abuzenadah, Ghazi A Damanhouri, Mohammed Al-Qahtani, Mohd A Beg
BACKGROUND: Currently, alternate plasticizers are used to replace phthalate plasticizers in children's toys, medical equipments and food packaging, due to the adverse effects of phthalate compounds on human health and laws prohibiting their use. Current information regarding the safety and potential adverse effects of alternate plasticizers is limited and recent studies have found alternate plasticizers to display similar characteristics to those observed in phthalate plasticizers. This study was undertaken to evaluate and predict the potential endocrine disrupting activity of the three most commonly used alternate plasticizers: di(2-ethylhexyl)terephthalate (DEHT), tris(2-ethylhexyl)trimellitate (TOTM), and diisononyl hexahydrophthalate (DINCH) against human sex hormone-binding globulin (SHBG) using in silico approaches...
September 30, 2016: BMC Structural Biology
David J Boerema, Valentina A Tereshko, Junliang Zhang, Stephen B H Kent
In this paper, we have used total chemical synthesis of RNase A analogues in order to probe the molecular basis of enzyme catalysis. Our goal was to obligately fill the adenine-binding pocket on the enzyme molecule, and to thus pre-orient the imidazole side chain of His(119) in its catalytically productive orientation. Two designed analogues of the RNase A protein molecule that contained an adenine moiety covalently bound to distinct amino acid side chains adjacent to the adenine binding pocket were prepared...
September 21, 2016: Organic & Biomolecular Chemistry
David R Janero, Ganesh A Thakur
Allosteric modulators of G-protein coupled receptors (GPCRs) hold the promise of improved pharmacology and safety over typical orthosteric GPCR ligands. These features are particularly relevant to the cannabinoid receptor 1 (CB1R) GPCR, since typical orthosteric CB1R ligands are associated with adverse events that limit their translational potential. Areas covered: The contextual basis for applying allostery to CB1R is considered from pharmacological, drug-discovery, and medicinal standpoints. Rational design of small-molecule CB1R allosteric modulators as potential pharmacotherapeutics would be greatly facilitated by direct experimental characterization of structure-function correlates underlying the biological activity of chemically-diverse CB1R allosteric modulators, CB1R allosteric ligand-binding binding pockets, and amino acid contact residues critical to allosteric ligand engagement and activity...
October 7, 2016: Expert Opinion on Drug Discovery
Emma L Summers, Christina D Moon, Renee Atua, Vickery L Arcus
Glycoside hydrolase (GH) family 29 consists solely of α-L-fucosidases. These enzymes catalyse the hydrolysis of glycosidic bonds. Here, the structure of GH29_0940, a protein cloned from metagenomic DNA from the rumen of a cow, has been solved, which reveals a multi-domain arrangement that has only recently been identified in bacterial GH29 enzymes. The microbial species that provided the source of this enzyme is unknown. This enzyme contains a second carbohydrate-binding domain at its C-terminal end in addition to the typical N-terminal catalytic domain and carbohydrate-binding domain arrangement of GH29-family proteins...
October 1, 2016: Acta Crystallographica. Section F, Structural Biology Communications
Li Fan, Wei Xiao
PCNA plays critical roles in DNA replication and various DNA repair pathways including DNA damage tolerance (DDT). In budding yeast Saccharomyces cerevisiae, DDT (aka DNA postreplication repair, PRR) is achieved by sequential ubiquitination of PCNA encoded by POL30. Our previous studies revealed that two Arabidopsis PCNA genes were able to complement the essential function of POL30 in budding yeast, but failed to rescue the PRR activity. Here we hypothesize that a certain amino acid variation(s) is responsible for the difference, and identified K196 as a critical residue for the PRR activity...
September 22, 2016: DNA Repair
Qurrat U Ain, Robert M Owen, Kiyoyuki Omoto, Rubben Torella, Krishna C Bulusu, David C Pryde, Robert C Glen, Julian E Fuchs, Andreas Bender
Selective modulators of the γ-amino butyric acid (GABAA) family of receptors have the potential to treat a range of disease states related to cognition, pain and anxiety. While the development of various α subunit-selective modulators is currently underway for the treatment of anxiety disorders, the mechanistic understanding of the correlation between their bioactivity and efficacy, based on ligand-target interactions, is currently still lacking. In order to alleviate this situation, in the current study we have analyzed, using ligand-based and structure-based methods, a dataset of 5,440 GABAA modulators...
October 5, 2016: Molecular Pharmaceutics
Nupur Bansal, Zheng Zheng, David S Cerutti, Kenneth M Merz
We review our performance in the SAMPL5 challenge for predicting host-guest binding affinities using the movable type (MT) method. The challenge included three hosts, acyclic Cucurbit[2]uril and two octa-acids with and without methylation at the entrance to their binding cavities. Each host was associated with 6-10 guest molecules. The MT method extrapolates local energy landscapes around particular molecular states and estimates the free energy by Monte Carlo integration over these landscapes. Two blind submissions pairing MT with variants of the KECSA potential function yielded mean unsigned errors of 1...
October 3, 2016: Journal of Computer-aided Molecular Design
Aping Mao, Jing Zhou, Bin Mao, Ya Zheng, Yufeng Wang, Daiqin Li, Pan Wang, Kaiyu Liu, Xiaoping Wang, Hui Ai
Pheromone-binding proteins (PBPs) are essential for the filtering, binding and transporting of sex pheromones across sensillum lymph to membrane-associated pheromone receptors of moths. In this study, three novel PBP genes were expressed in Escherichia coli to examine their involvement in the sex pheromone perception of Maruca vitrata. Fluorescence binding experiments indicated that MvitPBP1-3 had strong binding affinities with four sex pheromones. Moreover, molecular docking results demonstrated that six amino acid residues of three MvitPBPs were involved in the binding of the sex pheromones...
October 4, 2016: Scientific Reports
Thanh-Nhat Pham, Simon Bordage, Marc Pudlo, Céline Demougeot, Khac-Minh Thai, Corine Girard-Thernier
Arginases are enzymes that are involved in many human diseases and have been targeted for new treatments. Here a series of cinnamides was designed, synthesized and evaluated in vitro and in silico for their inhibitory activity against mammalian arginase. Using a microassay on purified liver bovine arginase (b-ARG I), (E)-N-(2-phenylethyl)-3,4-dihydroxycinnamide, also named caffeic acid phenylamide (CAPA), was shown to be slightly more active than our natural reference inhibitor, chlorogenic acid (IC50 = 6.9 ± 1...
2016: International Journal of Molecular Sciences
Safaa Dalla, Susanne Dobler
Herbivorous insects and their adaptations against plant toxins provide striking opportunities to investigate the genetic basis of traits involved in coevolutionary interactions. Target site insensitivity to cardenolides has evolved convergently across six orders of insects, involving identical substitutions in the Na,K-ATPase gene and repeated convergent gene duplications. The large milkweed bug, Oncopeltus fasciatus, has three copies of the Na,K-ATPase α-subunit gene that bear differing numbers of amino acid substitutions in the binding pocket for cardenolides...
September 29, 2016: Evolution; International Journal of Organic Evolution
Manuel Adrian Troncoso-Ponce, Guillaume Barthole, Geoffrey Tremblais, Alexandra To, Martine Miquel, Loic Lepiniec, Sébastien Baud
In angiosperms, double fertilization of the embryo sac initiates the development of the embryo and the endosperm. In Arabidopsis thaliana, an exalbuminous species, the endosperm is reduced to one cell layer during seed maturation and reserves such as oil are massively deposited in the enlarging embryo. Here, we consider the strikingly different fatty acid (FA) compositions of the oils stored in the two zygotic tissues. Endosperm oil is enriched in ω-7 monounsaturated FAs, that represent more than 20 Mol% of total FAs, whereas these molecular species are ten-fold less abundant in the embryo...
September 28, 2016: Plant Cell
D A Leiman, B P Riff, S Morgan, D C Metz, G W Falk, B French, C A Umscheid, J D Lewis
In patients with gastroesophageal reflux disease (GERD) and erosive esophagitis, treatment with proton pump inhibitors (PPIs) is highly effective. However, in some patients, especially those with non-erosive reflux disease or atypical GERD symptoms, acid suppressive therapy with PPIs is not as successful. Alginates are medications that work through an alternative mechanism by displacing the post-prandial gastric acid pocket. We performed a systematic review and meta-analysis to examine the benefit of alginate-containing compounds in the treatment of patients with symptoms of GERD...
September 26, 2016: Diseases of the Esophagus: Official Journal of the International Society for Diseases of the Esophagus
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