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https://www.readbyqxmd.com/read/29775064/enhancing-action-of-positive-allosteric-modulators-through-the-design-of-dimeric-compounds
#1
Thomas Drapier, Pierre Geubelle, Charlotte Bouckaert, Lise Nielsen, Saara Laulumaa, Eric Goffin, Sébastien Dilly, Pierre Francotte, Julien Hanson, Lionel Pochet, Jette Sandholm Kastrup, Bernard Pirotte
The present study describes the identification of highly potent dimeric 1,2,4-benzothiadiazine 1,1-dioxide (BTD)-type positive allosteric modulators of the AMPA receptors (AMPApams) obtained by linking two monomeric BTD scaffolds through their respective 6-positions. Using previous X-ray data from monomeric BTDs co-crystallized with the GluA2o ligand-binding domain (LBD), a molecular modeling approach was performed to predict the preferred dimeric combinations. Two 6,6-ethylene-linked dimeric BTD compounds (16 and 22) were prepared and evaluated as AMPApams on HEK293 cells expressing GluA2o(Q) (calcium flux experiment)...
May 18, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29772410/estrogenic-properties-of-coumarins-and-meroterpene-from-the-fruits-of-cullen-corylifolium-experimental-and-computational-studies
#2
Tiehua Zhang, Shuning Zhong, Ligang Hou, Tiezhu Li, XiaoJia Xing, Tianzhu Guan, Jie Zhang, Yongjun Wang
Coumarins and meroterpene from the fruits of Cullen corylifolium were evaluated for their ability to bind and activate human estrogen receptor α (hERα) by a combination of in vitro studies and molecular dynamics simulations. The recombinant hERα ligand binding domain (hERα-LBD) was produced in BL21 (DE3)pLysS and the fluorescence polarization (FP) assay was performed to determine the binding affinities of coumarins and meroterpene with receptor protein. These compounds displayed distinct binding potency toward hERα-LBD, generally increased with their increasing molecular length and Connolly solvent-excluded volume (CSEV)...
May 14, 2018: Phytochemistry
https://www.readbyqxmd.com/read/29764864/targeting-the-hsp40-hsp70-chaperone-axis-as-a-novel-strategy-to-treat-castration-resistant-prostate-cancer
#3
Michael A Moses, Yeong Sang Kim, Genesis M Rivera-Marquez, Nobu Oshima, Matthew J Watson, Kristin Beebe, Catherine Wells, Sunmin Lee, Abbey D Zuehlke, Hao Shao, William E Bingman, Vineet Kumar, Sanjay Malhotra, Nancy L Weigel, Jason E Gestwicki, Jane Trepel, Leonard M Neckers
Castration-resistant prostate cancer (CRPC) is characterized by reactivation of androgen receptor (AR) signaling in part by elevated expression of AR splice variants (ARv) including ARv7, a constitutively active, ligand binding domain (LBD)-deficient variant whose expression has been correlated with therapeutic resistance and poor prognosis. In a screen to identify small molecule dual inhibitors of both androgen-dependent and androgen-independent AR gene signatures, we identified the chalcone C86. Binding studies using purified proteins and CRPC cell lysates revealed C86 to interact with heat shock protein 40 (Hsp40)...
May 15, 2018: Cancer Research
https://www.readbyqxmd.com/read/29763311/thyroid-disruption-by-bisphenol-s-analogues-via-thyroid-hormone-receptor-%C3%AE-in-vitro-in-vivo-and-molecular-dynamics-simulation-study
#4
Liping Lu, Tingjie Zhan, Mei Ma, Chao Xu, Jingpeng Wang, Chunlong Zhang, Weiping Liu, Shulin Zhuang
Bisphenol S (4-hydroxyphenyl sulfone, BPS) is increasingly used as BPA alternatives. The global usage of BPS and its analogues (BPSs) caused the frequent detection of their residues in multiple environmental media. We investigated their potential endocrine disrupting effects toward thyroid hormone receptor (TR) β. The molecular interaction of BPSs toward TRβ ligand binding domain (LBD) was probed by fluorescence spectroscopy and molecular dynamics (MD) simulations. BPSs caused the static fluorescence quenching of TRβ LBD...
May 15, 2018: Environmental Science & Technology
https://www.readbyqxmd.com/read/29758259/structural-basis-for-polyamine-binding-at-the-dcache-domain-of-the-mcpu-chemoreceptor-from-pseudomonas-putida
#5
José Antonio Gavira, Álvaro Ortega, David Martín-Mora, María Teresa Conejero-Muriel, Andrés Corral-Lugo, Bertrand Morel, Miguel A Matilla, Tino Krell
Many bacteria can move chemotactically to a variety of compounds and the recognition of chemoeffectors by the chemoreceptor ligand binding domain (LBD) defines the specificity of response. Many chemoreceptors were found to recognize different amino- and organic acids, but the McpU chemoreceptor from Pseudomonas putida was identified as the first chemoreceptor that bound specifically polyamines. We report here the three-dimensional structure of McpU-LBD in complex with putrescine at a resolution of 2.4 Å, which fitted well a solution structure generated by Small Angle X-ray Scattering...
May 11, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29757018/a-current-structural-perspective-on-pxr-and-car-in-drug-metabolism
#6
Cameron D Buchman, Sergio C Chai, Taosheng Chen
Pregnane X receptor (PXR) and the constitutive androstane receptor (CAR) are two members of the nuclear receptor superfamily that play major roles in the expression of various drug metabolism enzymes and are known for their ligand promiscuity. As with other nuclear receptors, PXR and CAR are each composed of a ligand-binding domain (LBD) and a DNA-binding domain (DBD) connected by a hinge region. Areas covered: This review focuses on the information obtained over the last 15+ years from X-ray crystallography studies of the structure of PXR and CAR...
May 14, 2018: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/29748975/lysosomes-autophagosomes-and-alzheimer-pathology-in-dementia-with-lewy-body-disease
#7
Rowan Gurney, Yvonne S Davidson, Andrew C Robinson, Anna Richardson, Matthew Jones, Julie S Snowden, David M A Mann
A failure of protein degradation may underpin Lewy body disease (LBD) where α-synuclein is assimilated into the pathognomic Lewy bodies and Lewy neurites. We investigated histological alterations in lysosomes and autophagosomes in the substantia nigra (SN) and cingulate gyrus (CG) in 34 patients with LBD employing antibodies against phosphorylated α-synuclein and lysosomal (lysosomal associated membrane proteins 1 and 2 (LAMP-1 and LAMP-2), cathepsin D (CTSD)) and autophagosomal (microtubule-associated protein light chain 3α (LC3A)) proteins...
May 10, 2018: Neuropathology: Official Journal of the Japanese Society of Neuropathology
https://www.readbyqxmd.com/read/29748621/proteomic-profiling-identifies-key-coactivators-utilized-by-mutant-er%C3%AE-proteins-as-potential-new-therapeutic-targets
#8
Leah A Gates, Guowei Gu, Yue Chen, Aarti D Rohira, Jonathan T Lei, Ross A Hamilton, Yang Yu, David M Lonard, Jin Wang, Shu-Ping Wang, David G Edwards, Philip F Lavere, Jiangyong Shao, Ping Yi, Antrix Jain, Sung Yun Jung, Anna Malovannaya, Shunqiang Li, Jieya Shao, Robert G Roeder, Matthew J Ellis, Jun Qin, Suzanne A W Fuqua, Bert W O'Malley, Charles E Foulds
Approximately 75% of breast cancers are estrogen receptor alpha (ERα)-positive and are treatable with endocrine therapies, but often patients develop lethal resistant disease. Frequent mutations (10-40%) in the ligand-binding domain (LBD) codons in the gene encoding ERα (ESR1) have been identified, resulting in ligand-independent, constitutively active receptors. In addition, ESR1 chromosomal translocations can occur, resulting in fusion proteins that lack the LBD and are entirely unresponsive to all endocrine treatments...
May 11, 2018: Oncogene
https://www.readbyqxmd.com/read/29737547/bisphenol-a-bpa-binding-on-full-length-architectures-of-estrogen-receptor
#9
Yaquan Liu, Kaili Qu, Ying Hai, Chunyan Zhao
Previous research has shown that the major toxicity mechanism for many environment chemicals is binding with estrogen receptor (ER) and blocking endogenous estrogen access, including bisphenol A (BPA). However, the molecular level understanding the global consequence of BPA binding on the full-length architectures of ER is largely unknown, which is a necessary stage to evaluate estrogen-like toxicity of BPA. In the present work, the consequence of BPA on full-length architectures of ER was firstly modeled based on molecular dynamics, focusing on the cross communication between multi-domains including ligand binding domain (LBD) and DNA binding domain (DBD)...
May 8, 2018: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/29728618/defining-a-conformational-ensemble-that-directs-activation-of-ppar%C3%AE
#10
Ian M Chrisman, Michelle D Nemetchek, Ian Mitchelle S de Vera, Jinsai Shang, Zahra Heidari, Yanan Long, Hermes Reyes-Caballero, Rodrigo Galindo-Murillo, Thomas E Cheatham, Anne-Laure Blayo, Youseung Shin, Jakob Fuhrmann, Patrick R Griffin, Theodore M Kamenecka, Douglas J Kojetin, Travis S Hughes
The nuclear receptor ligand-binding domain (LBD) is a highly dynamic entity. Crystal structures have defined multiple low-energy LBD structural conformations of the activation function-2 (AF-2) co-regulator-binding surface, yet it remains unclear how ligand binding influences the number and population of conformations within the AF-2 structural ensemble. Here, we present a nuclear receptor co-regulator-binding surface structural ensemble in solution, viewed through the lens of fluorine-19 (19 F) nuclear magnetic resonance (NMR) and molecular simulations, and the response of this ensemble to ligands, co-regulator peptides and heterodimerization...
May 4, 2018: Nature Communications
https://www.readbyqxmd.com/read/29723544/alternative-dimerization-interfaces-in-the-glucocorticoid-receptor-%C3%AE-ligand-binding-domain
#11
Laurent Bianchetti, Bianca Wassmer, Audrey Defosset, Anna Smertina, Marion L Tiberti, Roland H Stote, Annick Dejaegere
BACKGROUND: Nuclear hormone receptors (NRs) constitute a large family of multi-domain ligand-activated transcription factors. Dimerization is essential for their regulation, and both DNA binding domain (DBD) and ligand binding domain (LBD) are implicated in dimerization. Intriguingly, the glucocorticoid receptor-α (GRα) presents a DBD dimeric architecture similar to that of the homologous estrogen receptor-α (ERα), but an atypical dimeric architecture for the LBD. The physiological relevance of the proposed GRα LBD dimer is a subject of debate...
April 30, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29718485/molecular-characterization-and-expression-of-vitellogenin-and-vitellogenin-receptor-of-thitarodes-pui-lepidoptera-hepialidae-an-insect-on-the-tibetan-plateau
#12
Han Wu, Feng-Ze Jiang, Ji-Xing Guo, Jie-Qun Yi, Jian-Bo Liu, Ying-Shuai Cao, Xue-Shuang Lai, Gu-Ren Zhang
Vitellogenin (Vg) and vitellogenin receptor (VgR) play important roles in the vitellogenesis of insects. In this study, we cloned and characterized the two corresponding genes (TpVg and TpVgR) in an economically important insect, Thitarodes pui (Lepidoptera: Hepialidae), from the Tibetan plateau. The full length of TpVg is 5566 bp with a 5373 bp open reading frame (ORF) encoding 1,790 amino acids. Sequence alignment revealed that TpVg has three conserved domains: a Vitellogenin_N domain, a DUF1943 domain, and a von Willebrand factor type D domain (VWD)...
March 1, 2018: Journal of Insect Science
https://www.readbyqxmd.com/read/29702556/multiple-isoforms-of-anti-lipopolysaccharide-factors-and-their-antimicrobial-functions-in-the-ridgetail-prawn-exopalaemon-carinicauda
#13
Xinjia Lv, Shihao Li, Chengsong Zhang, Jianhai Xiang, Fuhua Li
As a kind of antimicrobial peptides (AMP) in crustacean, anti-lipopolysaccharide factors (ALFs) have broad spectrum antimicrobial activities. In the present study, we identified four ALF genes, EcALF2-5 , from the ridgetail prawn Exopalaemon carinicauda . Tissue distribution analysis showed that EcALF2 and EcALF4 transcripts were mainly located in gill, epidermis, and stomach, while EcALF3 and EcALF5 were mainly in hemocytes. Peptides corresponding to the LPS binding domain (LBD) of EcALFs were synthesized for analyzing their antimicrobial activities...
April 27, 2018: Marine Drugs
https://www.readbyqxmd.com/read/29688519/a-possible-novel-mechanism-of-action-of-genistein-and-daidzein-for-activating-thyroid-hormone-receptor-tr-mediated-transcription
#14
Winda Ariyani, Toshiharu Iwasaki, Wataru Miyazaki, Yu Lu, Shigeki Takeda, Noriyuki Koibuchi
Thyroid hormone receptors (TRs) are members of the nuclear receptor superfamily that regulate their target genes for controlling organ development and functional maintenance. Soybean isoflavones, especially genistein and daidzein, modulate various hormone-mediated pathways. However, their effects on TRs have not yet been extensively studied. In this study, the effects of these isoflavones on TR action were evaluated using transient transfection-based reporter gene assays and molecular docking studies. Genistein and daidzein augmented T3-liganded TR-mediated transcription in a concentration-dependent manner...
April 23, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/29681137/lbd18-utilizes-a-dual-mode-of-a-positive-feedback-loop-to-regulate-arf-expression-and-transcriptional-activity-in-arabidopsis
#15
Shashank K Pandey, Han Woo Lee, Min-Jung Kim, Chuloh Cho, Eunkyoo Oh, Jungmook Kim
A hierarchy of transcriptional regulators controlling lateral root formation in Arabidopsis thaliana has been identified, including the AUXIN RESPONSE FACTOR(ARF)7/ARF19-LATERAL ORGAN BOUNDARIES DOMAIN(LBD)16/LBD18 transcriptional network. However, their feedback regulation mechanisms are not known. Here we show that LBD18 controls ARF activity using the dual mode of a positive feedback loop. We showed that ARF7 and ARF19 directly bind AuxRE in the LBD18 promoter. A variety of molecular and biochemical experiments demonstrated that LBD18 binds a specific DNA motif in the ARF19 promoter to regulate its expression in vivo as well as in vitro...
April 22, 2018: Plant Journal: for Cell and Molecular Biology
https://www.readbyqxmd.com/read/29667565/longitudinal-associations-between-different-dementia-diagnoses-and-medication-use-jointly-accounting-for-dropout
#16
George O Agogo, Christine M Ramsey, Danijela Gnjidic, Daniela C Moga, Heather Allore
ABSTRACTBackground:Longitudinal studies of older adults are characterized by high dropout rates, multimorbid conditions, and multiple medication use, especially proximal to death. We studied the association between multiple medication use and incident dementia diagnoses including Alzheimer's disease (AD), vascular dementia (VD), and Lewy-body dementia (LBD), simultaneously accounting for dropout. METHODS: Using the National Alzheimer's Coordinating Center data with three years of follow-up, a set of covariate-adjusted models that ignore dropout was fit to complete-case data, and to the whole-cohort data...
April 18, 2018: International Psychogeriatrics
https://www.readbyqxmd.com/read/29667121/backbone-1-h-13-c-and-15-n-resonance-assignments-of-the-ligand-binding-domain-of-the-human-wildtype-glucocorticoid-receptor-and-the-f602s-mutant-variant
#17
Christian Köhler, Göran Carlström, Stefan Tångefjord, Tineke Papavoine, Matti Lepistö, Karl Edman, Mikael Akke
The glucocorticoid receptor (GR) is a nuclear hormone receptor that regulates key genes controlling development, metabolism, and the immune response. GR agonists are efficacious for treatment of inflammatory, allergic, and immunological disorders. Steroid hormone binding to the ligand-binding domain (LBD) of GR is known to change the structural and dynamical properties of the receptor, which in turn control its interactions with DNA and various co-regulators and drive the pharmacological response. Previous biophysical studies of the GR LBD have required the use of mutant forms to overcome issues with limited protein stability and high aggregation propensity...
April 17, 2018: Biomolecular NMR Assignments
https://www.readbyqxmd.com/read/29656875/structural-mechanism-of-functional-modulation-by-gene-splicing-in-nmda-receptors
#18
Michael C Regan, Timothy Grant, Miranda J McDaniel, Erkan Karakas, Jing Zhang, Stephen F Traynelis, Nikolaus Grigorieff, Hiro Furukawa
Alternative gene splicing gives rise to N-methyl-D-aspartate (NMDA) receptor ion channels with defined functional properties and unique contributions to calcium signaling in a given chemical environment in the mammalian brain. Splice variants possessing the exon-5-encoded motif at the amino-terminal domain (ATD) of the GluN1 subunit are known to display robustly altered deactivation rates and pH sensitivity, but the underlying mechanism for this functional modification is largely unknown. Here, we show through cryoelectron microscopy (cryo-EM) that the presence of the exon 5 motif in GluN1 alters the local architecture of heterotetrameric GluN1-GluN2 NMDA receptors and creates contacts with the ligand-binding domains (LBDs) of the GluN1 and GluN2 subunits, which are absent in NMDA receptors lacking the exon 5 motif...
April 10, 2018: Neuron
https://www.readbyqxmd.com/read/29651518/updating-impairments-and-the-failure-to-explore-new-hypotheses-following-right-brain-damage
#19
Elisabeth Stöttinger, Carolyn Louise Guay, James Danckert, Britt Anderson
We have shown recently that damage to the right hemisphere impairs the ability to update mental models when evidence suggests an old model is no longer appropriate. We argue that this deficit is generic in the sense that it crosses multiple cognitive and perceptual domains. Here, we examined the nature of this updating impairment to determine more precisely the underlying mechanisms. We had right (RBD, N = 12) and left brain damaged (LBD, N = 10) patients perform versions of our picture-morphing task in which pictures gradually morph from one object (e...
April 12, 2018: Experimental Brain Research. Experimentelle Hirnforschung. Expérimentation Cérébrale
https://www.readbyqxmd.com/read/29629495/lewy-body-disease-clinical-and-pathological-overlap-syndrome-between-synucleinopathies-parkinson-disease-and-tauopathies-alzheimer-disease
#20
REVIEW
Clovis Foguem, Patrick Manckoundia
Lewy body disease (LBD) is a neurodegenerative disease resulting in dementia. It shares clinical and pathological features with Parkinson disease (PD), the most frequent synucleinopathy, Parkinson disease dementia (PDD), and Alzheimer disease (AD), a tauopathy. Even though the diagnostic criteria for these neurodegenerative diseases are clearly established, and recently revised for LBD, their precise clinical diagnosis is often difficult because LBD, PD, PDD, and AD share epidemiological, clinical, and pathological characteristics...
April 8, 2018: Current Neurology and Neuroscience Reports
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