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https://www.readbyqxmd.com/read/27923202/structure-based-optimization-of-salt-bridge-network-across-the-complex-interface-of-ptpn4-pdz-domain-with-its-peptide-ligands-in-neuroglioma
#1
Xian Xiao, Qiang-Hua He, Li-Yan Yu, Song-Qing Wang, Yang Li, Hua Yang, Ai-Hua Zhang, Xiao-Hong Ma, Yu-Jie Peng, Bing Chen
The PTP non-receptor type 4 (PTPN4) is an important regulator protein in learning, spatial memory and cerebellar synaptic plasticity; targeting the PDZ domain of PTPN4 has become as attractive therapeutic strategy for human neuroglioma. Here, we systematically examined the complex crystal structures of PTPN4 PDZ domain with its known peptide ligands; a number of charged amino acid residues were identified in these ligands and in the peptide-binding pocket of PDZ domain, which can constitute a complicated salt-bridge network across the complex interface...
November 30, 2016: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/27922847/apolipoprotein-e-metabolism-and-functions-in-brain-and-its-role-in-alzheimer-s-disease
#2
Fan Liao, Hyejin Yoon, Jungsu Kim
PURPOSE OF REVIEW: APOE4 genotype is the strongest genetic risk factor for Alzheimer's disease. Prevailing evidence suggests that amyloid β plays a critical role in Alzheimer's disease. The objective of this article is to review the recent findings about the metabolism of apolipoprotein E (ApoE) and amyloid β and other possible mechanisms by which ApoE contributes to the pathogenesis of Alzheimer's disease. RECENT FINDINGS: ApoE isoforms have differential effects on amyloid β metabolism...
December 5, 2016: Current Opinion in Lipidology
https://www.readbyqxmd.com/read/27922830/ligand-receptor-binding-kinetics-in-surface-plasmon-resonance-cells-a-monte-carlo-analysis
#3
Jacob Carroll, Matthew Raum, Kimberly Forsten-Williams, Uwe C Täuber
Surface plasmon resonance (SPR) chips are widely used to measure association and dissociation rates for the binding kinetics between two species of chemicals, e.g., cell receptors and ligands. It is commonly assumed that ligands are spatially well mixed in the SPR region, and hence a mean-field rate equation description is appropriate. This approximation however ignores the spatial fluctuations as well as temporal correlations induced by multiple local rebinding events, which become prominent for slow diffusion rates and high binding affinities...
December 6, 2016: Physical Biology
https://www.readbyqxmd.com/read/27922213/quantitative-maldi-ms-binding-assays-an-alternative-to-radiolabeling
#4
Maxime Rossato, Guillaume Miralles, Céline M'Kadmi, Mathieu Maingot, Muriel Amblard, Bernard Mouillac, Didier Gagne, Jean Martinez, Gilles Subra, Christine Enjalbal, Sonia Cantel
Radiolabeling of ligands is still the gold standard in the study of high-affinity receptor-ligand interactions. In an effort toward safer and simpler alternatives to the use of radioisotopes, we developed a quantitative and highly sensitive matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS) method that relies on the use of chemically tagged ligands designed to be specifically detectable when present as traces in complex biological mixtures such as cellular lysates. This innovative technology allows easy, sensitive detection and accurate quantification of analytes at the sub-nanomolar level...
December 6, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27922200/a-fluorescence-lifetime-based-binding-assay-for-class-iia-histone-deacetylases
#5
Christian Meyners, Monique Mertens, Pablo Wessig, Franz-Josef Meyer-Almes
Class IIa HDACs show extremely low enzymatic activity and no commonly accepted endogenous substrate is known today. Increasing evidence suggests that these enzymes exert their effect rather through molecular recognition of acetylated proteins and recruiting other proteins like HDAC3 to the desired target location. Accordingly, class IIa HDACs like bromodomains have been suggested to act as "Readers" of acetyl marks, whereas enzymatically active HDACs from class I or IIb are called "Erasers" to highlight their capability to remove acetyl groups from acetylated histones or other proteins...
December 6, 2016: Chemistry: a European Journal
https://www.readbyqxmd.com/read/27922023/systematic-site-directed-mutagenesis-of-the-helicobacter-pylori-cagl-protein-of-the-cag-type-iv-secretion-system-identifies-novel-functional-domains
#6
Tobias Bönig, Patrick Olbermann, Simon H Bats, Wolfgang Fischer, Christine Josenhans
The Cag Type IV secretion system, which contributes to inflammation and cancerogenesis during chronic infection, is one of the major virulence factors of the bacterial gastric pathogen Helicobacter pylori. We have generated and characterized a series of non-marked site-directed chromosomal mutants in H. pylori to define domains of unknown function of the essential tip protein CagL of the Cag secretion system. Characterizing the CagL mutants, we determined that their function to activate cells and transport the effector CagA was reduced to different extents...
December 6, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27921334/synacton-and-individual-activity-of-synthetic-and-natural-corticotropins
#7
T V Vyunova, L A Andreeva, K V Shevchenko, N F Myasoedov
Short endogenous peptides represent one of the most important constituents of the mammalian body's general regulatory system. Some synthesized analogs and modified natural peptides (eg, corticotropins) also show high biological activity. Nevertheless, the mechanism of action of regulatory peptides remains unclear. To explain the effects of peptides of intermolecular processes, the hypothesis that a synactonal mechanism underlies the action of regulatory peptides, exemplified by the heptapeptide Semax, has been proposed...
December 6, 2016: Journal of Molecular Recognition: JMR
https://www.readbyqxmd.com/read/27921041/signaling-crosstalk-between-tubular-epithelial-cells-and-interstitial-fibroblasts-after-kidney-injury
#8
REVIEW
Roderick J Tan, Dong Zhou, Youhua Liu
BACKGROUND: A wide variety of kidney diseases ultimately lead to tubulointerstitial damage. The initial site of injury is usually the renal tubules, with activation of fibroblasts occurring later. Self-limited disease is characterized by transient cellular activation with timed deactivation and ultimately a return to normal functioning, whereas sustained responses characterize chronic disease and the development of irreversible fibrosis. The underlying molecular and cellular mechanisms of this cascade of events remain an area of active research...
October 2016: Kidney Diseases
https://www.readbyqxmd.com/read/27920295/a-novel-transcriptional-regulator-related-to-thiamine-phosphate-synthase-controls-thiamine-metabolism-genes-in-archaea
#9
Dmitry A Rodionov, Semen A Leyn, Xiaoqing Li, Irina A Rodionova
: Thiamine (vitamin B1) is a precursor of thiamine pyrophosphate (TPP), an essential coenzyme in the central metabolism of all living organisms. Bacterial thiamin biosynthesis and salvage genes are controlled at the RNA level by TPP-responsive riboswitches. In Archaea, TPP riboswitches are restricted to the Thermoplasmatales order. Mechanisms of transcriptional control of thiamine genes in other archaeal lineages remain unknown. Using the comparative genomics approach, we identified a novel family of transcriptional regulators (named ThiR) controlling thiamine biosynthesis and transport genes in diverse lineages from the Crenarchaeota phylum, as well as in the Halobacteria and Thermococci classes of the Euryarchaeota ThiR regulators are composed of an N-terminal DNA-binding domain and a C-terminal ligand-binding domain that is similar to the archaeal thiamin phosphate synthase ThiN...
December 5, 2016: Journal of Bacteriology
https://www.readbyqxmd.com/read/27920218/a-molecular-basis-for-the-presentation-of-phosphorylated-peptides-by-hla-b-antigens
#10
Adán Alpízar, Fabio Marino, Antonio Ramos-Fernández, Manuel Lombardía, Anita Jeko, Florencio Pazos, Alberto Paradela, César Santiago, Albert J R Heck, Miguel Marcilla
As aberrant protein phosphorylation is a hallmark of tumor cells, the display of tumor-specific phosphopeptides by Human Leukocyte Antigen (HLA) class I molecules can be exploited in the treatment of cancer by T-cell-based immunotherapy. Yet, the characterization and prediction of HLA-I phospholigands is challenging as the molecular determinants of the presentation of such post-translationally modified peptides are not fully understood. Here, we employed a peptidomic workflow to identify 256 unique phosphorylated ligands associated with HLA-B*40, -B*27, -B*39 or -B*07...
December 5, 2016: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/27920204/studies-on-the-detection-expression-glycosylation-dimerization-and-ligand-binding-properties-of-mouse-siglec-e
#11
Shoib Siddiqui, Flavio Schwarz, Stevan Springer, Zahra Khedri, Hai Yu, Lingquan Deng, Andrea Verhagen, Yuko Naito-Matsui, Weiping Jiang, Daniel Kim, Jie Zhou, Beibei Ding, Xi Chen, Nissi Varki, Ajit Varki
CD33-related Siglecs are a family of proteins widely expressed on innate immune cells. Binding of sialylated glycans or other ligands triggers signals that inhibit or activate inflammation. Immunomodulation by Siglecs has been extensively studied, but relationships between structure and functions are poorly explored. Here we present new data relating the structure and function of Siglec-E, the major CD33-related Siglec expressed on mouse neutrophils, monocytes, macrophages, and dendritic cells. We generated nine new rat monoclonal antibodies specific to mouse Siglec-E, with no cross-reactivity to Siglec-F...
December 5, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27920201/the-streptococcus-gordonii-adhesin-csha-binds-host-fibronectin-via-a-catch-clamp-mechanism
#12
Catherine R Back, Maryta N Sztukowska, Marisa Till, Richard J Lamont, Howard F Jenkinson, Angela H Nobbs, Paul R Race
Adherence of bacteria to biotic or abiotic surfaces is a prerequisite for host colonization and represents an important step in microbial pathogenicity. This attachment is facilitated by bacterial adhesins at the cell surface. Due to their size and often elaborate multi-domain architectures, these polypeptides represent challenging targets for detailed structural and functional characterization. The multifunctional fibrillar adhesin CshA, which mediates binding to both host molecules and other microorganisms, is an important determinant of colonisation by Streptococcus gordonii, an oral commensal and opportunistic pathogen of animals and humans...
December 5, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27919657/synthesis-of-novel-steroidal-agonists-partial-agonists-and-antagonists-for-the-glucocorticoid-receptor
#13
Zhuang Jin, Hua Lin, Sathish Srinivasan, Jerome C Nwachukwu, Nelson Bruno, Patrick R Griffin, Kendall W Nettles, Theodore M Kamenecka
Adverse effects of glucocorticoids could be limited by developing new compounds that selectively modulate anti-inflammatory activity of the glucocorticoid receptor (GR). We have synthesized a novel series of steroidal GR ligands, including potent agonists, partial agonists and antagonists with a wide range of effects on inhibiting secretion of interleukin-6. Some of these new ligands were designed to directly impact conformational stability of helix-12, in the GR ligand-binding domain (LBD). These compounds modulated GR activity and glucocorticoid-induced gene expression in a manner that was inversely correlated to the degree of inflammatory response...
November 15, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27919612/an-in-tether-sulfoxide-chiral-center-influences-the-biophysical-properties-of-the-n-capped-peptides
#14
Jingxu Li, Yuan Tian, Dongyuan Wang, Yujie Wu, Xiyang Ye, Zigang Li
Thanks to their large binding interfaces, peptides are attractive ligands targeting protein-protein interactions compared with small molecules. Various strategies to improve peptides' pharmaceutical properties have been developed to constrain peptides into their functional three-dimensional structures. In our previous work, we reported that an in-tether chiral center could modulate peptides' biophysical properties. Herein, we applied this concept to construct a chiral sulfoxide center into the N-terminal end-cap system...
November 25, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27918994/importance-of-5-6-aryl-substitution-on-the-pharmacological-profile-of-4-2-propyl-1h-benzo-d-imidazol-1-yl-methyl-1-1-biphenyl-2-carboxylic-acid-derived-ppar%C3%AE-agonists
#15
Victoria Obermoser, Robert Mauersberger, Daniela Schuster, Monika Czifersky, Marina Lipova, Monika Siegl, Ulrich Kintscher, Ronald Gust
In this structure-activity relationship study, the influence of aryl substituents at position 5 or 6 on the pharmacological profile of the partial PPARγ agonist 4'-((2-propyl-1H-benzo[d]imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carboxylic acid was investigated. This lead was previously identified as the essential part of telmisartan to induce PPARγ activation. Para-OCH3-phenyl substitution strongly increased potency and efficacy independent of the position. Both compounds represent full agonists because of strong hydrophobic contacts with the amino acid Phe363 in the ligand binding domain...
November 25, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27918632/copper-zinc-thiolate-complexes-as-potential-molecular-precursors-for-copper-zinc-tin-sulfide-czts
#16
Daniel Fuhrmann, Stefan Dietrich, Harald Krautscheid
Five copper zinc thiolate complexes [(iPr3PCu)2(ZnEt2)(edt)]2 (1-Et), [(iPr3PCu)2(Zn(iPr)2)(edt)]2 (1-iPr), [(iPr3PCu)4(edt)2(ZnMe2)]2 (2), [(iPr3PCu)3(ZnPh2)(ZnPh)(edt)2]2 (3) and [(iPr3PCu)2Zn2(edt)3]6 (4) were prepared by the reaction of [(iPr3PCu)2(edt)]2 with ZnR2 (R = Me, Et, Ph, iPr) with or without addition of ethanedithiol (edt2- = ethane-1,2-dithiolate). The molecular structures of these complexes were determined by single crystal X-ray diffraction. The ethanedithiolate ligands coordinate in µ3-eta1:eta2:eta1 (2, 4), µ4-eta1:eta1:eta2:eta1 (1-R, 3) and µ5-eta1:eta1:eta2:eta1:eta1 (2) bridging mode, each sulfur atom binds to two or three metal atoms...
December 5, 2016: Chemistry: a European Journal
https://www.readbyqxmd.com/read/27918051/detection-of-zn-2-release-in-nitric-oxide-treated-cells-and-proteome-dependence-on-fluorescent-sensor-and-proteomic-sulfhydryl-groups
#17
Mohammad R Karim, David H Petering
Nitric oxide (NO) is both an important regulatory molecule in biological systems and a toxic xenobiotic. Its oxidation products react with sulfhydryl groups and either nitrosylate or oxidize them. The aerobic reaction of NO supplied by diethylamine NONOate (DEA-NO) with pig kidney LLC-PK1 cells and Zn-proteins within the isolated proteome was examined with three fluorescent zinc sensors, zinquin (ZQ), TSQ, and FluoZin-3 (FZ-3). Observations of Zn(2+) labilization from Zn-proteins depended on the specific sensor used...
December 5, 2016: Metallomics: Integrated Biometal Science
https://www.readbyqxmd.com/read/27917940/ubiquitin-ligase-nedd4-regulates-ppar%C3%AE-stability-and-adipocyte-differentiation-in-3t3-l1-cells
#18
Jing Jing Li, Ruishan Wang, Rati Lama, Xinjiang Wang, Z Elizabeth Floyd, Edwards A Park, Francesca-Fang Liao
Peroxisome proliferator-activated receptor-γ (PPARγ) is a ligand-activated nuclear receptor which controls lipid and glucose metabolism. It is also the master regulator of adipogenesis. In adipocytes, ligand-dependent PPARγ activation is associated with proteasomal degradation; therefore, regulation of PPARγ degradation may modulate its transcriptional activity. Here, we show that neural precursor cell expressed developmentally down-regulated protein 4 (NEDD4), an E3 ubiquitin ligase, interacts with the hinge and ligand binding domains of PPARγ and is a bona fide E3 ligase for PPARγ...
December 5, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27917874/discovery-synthesis-biological-evaluation-and-structure-based-optimization-of-novel-piperidine-derivatives-as-acetylcholine-binding-protein-ligands
#19
Jian Shen, Xi-Cheng Yang, Ming-Cheng Yu, Li Xiao, Xun-Jie Zhang, Hui-Jiao Sun, Hao Chen, Guan-Xin Pan, Yu-Rong Yan, Si-Chen Wang, Wei Li, Lu Zhou, Qiong Xie, Lin-Qian Yu, Yong-Hui Wang, Li-Ming Shao
The homomeric α7 nicotinic receptor (α7 nAChR) is widely expressed in the human brain that could be activated to suppress neuroinflammation, oxidative stress and neuropathic pain. Consequently, a number of α7 nAChR agonists have entered clinical trials as anti-Alzheimer's or anti-psychotic therapies. However, high-resolution crystal structure of the full-length α7 receptor is thus far unavailable. Since acetylcholine-binding protein (AChBP) from Lymnaea stagnalis is most closely related to the α-subunit of nAChRs, it has been used as a template for the N-terminal domain of α-subunit of nAChR to study the molecular recognition process of nAChR-ligand interactions, and to identify ligands with potential nAChR-like activities...
December 5, 2016: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/27917863/dna-intercalation-optimized-by-two-step-molecular-lock-mechanism
#20
Ali A Almaqwashi, Johanna Andersson, Per Lincoln, Ioulia Rouzina, Fredrik Westerlund, Mark C Williams
The diverse properties of DNA intercalators, varying in affinity and kinetics over several orders of magnitude, provide a wide range of applications for DNA-ligand assemblies. Unconventional intercalation mechanisms may exhibit high affinity and slow kinetics, properties desired for potential therapeutics. We used single-molecule force spectroscopy to probe the free energy landscape for an unconventional intercalator that binds DNA through a novel two-step mechanism in which the intermediate and final states bind DNA through the same mono-intercalating moiety...
December 5, 2016: Scientific Reports
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