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Ulf Guendisch, Jessica Weiss, Florence Ecoeur, Julia Christina Riker, Klemens Kaupmann, Joerg Kallen, Samuel Hintermann, David Orain, Janet Dawson, Andreas Billich, Christine Guntermann
Retinoic acid receptor-related-orphan-receptor-C (RORγt) is the key transcription factor that is driving the differentiation of IL-17 producing T-helper 17 (Th17) cells that are implicated in the pathology of various autoimmune and inflammatory diseases. Based on the importance of RORγt in promoting Th17-driven pathology, there is considerable interest to develop low-molecular-weight compounds with the aim of inhibiting the transcriptional activity of this nuclear hormone receptor. In this article, we describe the in vitro and in vivo pharmacology of a potent and selective small-molecular-weight RORγt inverse agonist...
2017: PloS One
Jie Zhang, Tiezhu Li, Tuoyi Wang, Cuiping Yuan, Shuning Zhong, Tianzhu Guan, Zhuolin Li, Yongzhi Wang, Hansong Yu, Quan Luo, Yongjun Wang, Tiehua Zhang
The binding interactions of bisphenol A (BPA) and its halogenated derivatives (halogenated BPAs) to human estrogen receptor α ligand binding domain (hERα-LBD) was investigated using a combined in vitro and in silico approach. First, the recombinant hERα-LBD was prepared as a soluble protein in Escherichia coli BL21(DE3)pLysS. A native fluorescent phytoestrogen, coumestrol, was employed as tracer for the fluorescence polarization assay. The results of the in vitro binding assay showed that bisphenol compounds could bind to hERα-LBD as the affinity ligands...
November 20, 2017: Archives of Toxicology
Ryota Shizu, Jungki Min, Mack Sobhany, Lars C Pedersen, Shingo Mutoh, Masahiko Negishi
The nuclear protein constitutive active/androstane receptor (CAR or NR1I3) regulates several liver functions such as drug and energy metabolism and cell growth or death, which are often involved in the development of diseases such as diabetes and hepatocellular carcinoma. CAR undergoes a conversion from inactive homodimers to active heterodimers with retinoid X receptor alpha (RXRα), and phosphorylation of the DNA-binding domain (DBD) at Thr-38 in CAR regulates this conversion. Here, we uncovered the molecular mechanism by which this phosphorylation regulates the intramolecular interaction between CARs DBD and ligand-binding domain (LBD), enabling the homodimer-heterodimer conversion...
November 13, 2017: Journal of Biological Chemistry
Jie Zhang, Tiezhu Li, Tuoyi Wang, Tianzhu Guan, Hansong Yu, Zhuolin Li, Yongzhi Wang, Yongjun Wang, Tiehua Zhang
The binding of bisphenol A (BPA) and its halogenated derivatives (halogenated BPAs) to mouse peroxisome proliferator-activated receptor α ligand binding domain (mPPARα-LBD) was examined by a combination of in vitro investigation and in silico simulation. Fluorescence polarization (FP) assay showed that halogenated BPAs could bind to mPPARα-LBD* as the affinity ligands. The calculated electrostatic potential (ESP) illustrated the different charge distributions of halogenated BPAs with altered halogenation patterns...
November 8, 2017: Toxicology Letters
Zhi Wang, Baozhen Sun, Fei Zhu
Previously, we found that the expression of several genes, including HR, varied in Drosophila melanogaster after white spot syndrome virus (WSSV) infection. In this present study, we further investigated the role of HR in Kuruma shrimp, Marsupenaeus japonicus and determined its anti-apoptosis and anti-inflammation role in the innate immune system. We successfully identified a partial sequence (866 bp in length) of the M. japonicus hormone receptor ligand binding domain (mjHR_LBD/mjHR). The 5' end of mjHR was successfully obtained; the open reading frame (ORF) ran from 33 to 701 bp, and encoded a protein containing 222 amino acids...
November 8, 2017: Fish & Shellfish Immunology
Jeremy Yang Lee, Richelle Baker, Pieter Coenen, Leon Straker
Prolonged standing is common in many occupations and has been associated with low back discomfort (LBD). No recent studies have investigated a footrest as an intervention to reduce LBD associated with prolonged standing. This study investigated the effect of a footrest on LBD and sought to determine if LBD changes were accompanied by changes in muscle fatigue and low back end-range posture and movement. Twenty participants stood for two 2-h trials, one with and one without a footrest. LBD, lumbar erector spinae electromyography, upper lumbar (UL) and lower lumbar (LL) angles were measured...
February 2018: Applied Ergonomics
Chongyi Xu, Huifen Cao, Enjun Xu, Shiqi Zhang, Yuxin Hu
Auxin-induced callus formation represents an important cell reprograming process during in vitro regeneration of plants, in which the pericycle or pericycle-like cells within plant organs are reprogramed into the pluripotent cell mass termed callus that is generally required for subsequent regeneration of root or shoot. However, the molecular events behind cell reprograming during auxin-induced callus formation are largely elusive. We previously identified that auxin-induced LBD transcription factors act as the master regulators to trigger auxin-induced callus formation...
November 7, 2017: Plant & Cell Physiology
Hiroki Mano, Shinichi Ikushiro, Nozomi Saito, Atsushi Kittaka, Toshiyuki Sakaki
Split-luciferase techniques are widely used to detect protein-protein interaction and bioactive small molecules including some hormones and vitamins. Previously, we successfully expressed chimeric proteins of luciferase and the ligand binding domain (LBD) of the vitamin D receptor (VDR), LucC-LBD-LucN in COS-7 cells. The LucC-LBD-LucN biosensor was named split-luciferase vitamin D biosensor (SLDB). This biosensor can detect and discriminate between VDR agonists and antagonists in mammalian cells. In this study, we established an in vitro screening system for VDR ligands using the SLDB proteins expressed in Escherichia coli (E...
October 31, 2017: Journal of Steroid Biochemistry and Molecular Biology
Michael J Firbank, John T O'Brien, John Paul Taylor
A significant symptom of Lewy body dementia (LBD) is slow cognitive processing or bradyphrenia. In a previous fMRI task-based study, we found slower responses in LBD, accompanied by greater deactivation in the default mode network. In this study, we investigated the timing and magnitude of the activations and deactivations with respect to reaction time to determine whether the slower responses in LBD were associated with delayed neuronal activity. Using fMRI, we examined the magnitude and latency of activations and deactivations during an event-related attention task in 32 patients with LBD and 23 healthy controls using predefined regions of interest...
November 2, 2017: Human Brain Mapping
Sabina Yasmin, Fabio Capone, Antonio Laghezza, Fabrizio Dal Piaz, Fulvio Loiodice, Viswanathan Vijayan, Velmurugan Devadasan, Susanta K Mondal, Özlem Atlı, Merve Baysal, Ashok K Pattnaik, Venkatesan Jayaprakash, Antonio Lavecchia
Peroxisome proliferator-activated receptor γ (PPARγ) has received significant attention as a key regulator of glucose and lipid homeostasis. In this study, we synthesized and tested a library of novel 5-benzylidene-thiazolidin-2,4-dione (BTZD) derivatives bearing a substituent on nitrogen of TZD nucleus (compounds 1a-1k, 2i-10i, 3a, 6a, and 8a-10a). Three compounds (1a, 1i, and 3a) exhibited selectivity towards PPARγ and were found to be weak to moderate partial agonists. Surface Plasmon Resonance (SPR) results demonstrated binding affinity of 1a, 1i and 3a towards PPARγ...
October 31, 2017: Scientific Reports
Haroon Latif Khan, Shahzad Bhatti, Sana Abbas, Yousaf Latif Khan, Muhammad Aslamkhan, Rosa Maria Marquez Gonzalez, Gerardo Rodriguez Gonzalez, Hikmet Hakan Aydin, Magali Segundo Trinidad
Androgen mediating signaling is implicated in regulating the expression of reproductive related genes. Any deviation in the gene expression might be the ignitable precursor for genomic instability that inflames the genomic rearrangements and a leading cause of cancer. The main goal of this study was to determine the relationships between trinucleotide repeats of androgen receptor (AR), sex steroids, and sexual function in men presenting with reduced sperm motility. We investigated the singleton or combinatorial effects of the length of trinucleotide repeats of AR on reproductive hormones, clinical parameters, semen analyses, as well as sexual assessment function of 210 asthenospermic outpatients along with 125 normal subjects...
October 30, 2017: Systems Biology in Reproductive Medicine
Mayra A Machuca, Kevin S Johnson, Yu C Liu, David L Steer, Karen M Ottemann, Anna Roujeinikova
It is recently appreciated that many bacterial chemoreceptors have ligand-binding domains (LBD) of the dCACHE family, a structure with two PAS-like subdomains, one membrane-proximal and the other membrane-distal. Previous studies had implicated only the membrane-distal subdomain in ligand recognition. Here, we report the 2.2 Å resolution crystal structure of dCACHE LBD of the Helicobacter pylori chemoreceptor TlpC. H. pylori tlpC mutants are outcompeted by wild type during stomach colonisation, but no ligands had been mapped to this receptor...
October 26, 2017: Scientific Reports
Álvaro Ortega, Igor B Zhulin, Tino Krell
Chemoreceptors in bacteria detect a variety of signals and feed this information into chemosensory pathways that represent a major mode of signal transduction. The five chemoreceptors from Escherichia coli have served as traditional models in the study of this protein family. Genome analyses revealed that many bacteria contain much larger numbers of chemoreceptors with broader sensory capabilities. Chemoreceptors differ in topology, sensing mode, cellular location, and, above all, the type of ligand binding domain (LBD)...
December 2017: Microbiology and Molecular Biology Reviews: MMBR
Alvin Yu, Albert Y Lau
Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that are responsible for the majority of excitatory transmission at the synaptic cleft. Mechanically speaking, agonist binding to the ligand binding domain (LBD) activates the receptor by triggering a conformational change that is transmitted to the transmembrane region, opening the ion channel pore. We use fully atomistic molecular dynamics simulations to investigate the binding process in the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, an iGluR subtype...
November 9, 2017: Journal of Physical Chemistry. B
Dominik Dreier, Simone Latkolik, Lukas Rycek, Michael Schnürch, Andrea Dymáková, Atanas G Atanasov, Angela Ladurner, Elke H Heiss, Hermann Stuppner, Daniela Schuster, Marko D Mihovilovic, Verena M Dirsch
The nuclear receptors peroxisome proliferator-activated receptor γ (PPARγ) and its hetero-dimerization partner retinoid X receptor α (RXRα) are considered as drug targets in the treatment of diseases like the metabolic syndrome and diabetes mellitus type 2. Effort has been made to develop new agonists for PPARγ to obtain ligands with more favorable properties than currently used drugs. Magnolol was previously described as dual agonist of PPARγ and RXRα. Here we show the structure-based rational design of a linked magnolol dimer within the ligand binding domain of PPARγ and its synthesis...
October 20, 2017: Scientific Reports
Mingsheng Xie, Hui Zhao, Qisong Liu, Yujia Zhu, Feng Yin, Yujie Liang, Yanhong Jiang, Dongyuan Wang, Kuan Hu, Xuan Qin, Zichen Wang, Yujie Wu, Naihan Xu, Xiyang Ye, Tao Wang, Zigang Li
Direct inhibition of the protein-protein interaction of ERα and its endogenous coactivators with a cell permeable stabilized peptide may offer a novel, promising strategy for combating ERα positive breast cancers. Here, we report the co-crystal structure of a helical peptide stabilized by a N-terminal unnatural cross-linked aspartic acid (TD) in complex with the ERα ligand binding domain (LBD). We designed a series of peptides and peptide 6 that showed direct and high-affinity binding to ERα with selective antiproliferative activity in ERα positive breast cancer cells...
October 31, 2017: Journal of Medicinal Chemistry
Eunkyeong Jeon, Na Young Kang, Chuloh Cho, Pil Joon Seo, Mi Chung Suh, Jungmook Kim
The LATERAL ORGAN BOUNDARIES (LOB) DOMAIN/ASYMMETRIC LEAVES2-LIKE (LBD/ASL) gene family members play key roles in diverse aspects of plant development. Previous studies have shown that LBD16, 18, 29, and 33 are critical for integrating the plant hormone auxin to control lateral root development in Arabidopsis thaliana. In the present study, we show that LBD14 is expressed exclusively in the root where it promotes lateral root (LR) emergence. Repression of LBD14 expression by ABA correlates with the inhibitory effects of ABA on LR emergence...
October 11, 2017: Plant & Cell Physiology
Manish Verma, Jason Callio, P Anthony Otero, Israel Sekler, Zachary P Wills, Charleen T Chu
Mutations in leucine-rich repeat kinase 2 (LRRK2) contribute to development of late-onset familial Parkinson's disease (PD), with clinical features of motor and cognitive dysfunction indistinguishable from sporadic PD. Calcium dysregulation plays an important role in PD pathogenesis, but the mechanisms of neurodegeneration remain unclear. Recent reports indicate enhanced excitatory neurotransmission in cortical neurons expressing mutant LRRK2, which occurs prior to the well-characterized phenotype of dendritic shortening...
October 16, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Li Zhang, Yaru Jin, Zhihua Han, Hongling Liu, Laihao Shi, Xiaoxue Hua, Jon A Doering, Song Tang, John P Giesy, Hongxia Yu
BDE-99 is one of the most abundant PBDEs, which due to its potential persistence and bioaccumulation occurs in aquatic wildlife. Previous studies in mammals have shown that BDE-99 affected development and disrupted certain endocrine functions through signaling pathways mediated by nuclear receptors (NRs). However, fewer studies have investigated the potential of BDE-99 to interact with NRs in aquatic vertebrates, such as fish. In the present study, interactions between BDE-99 and NRs were investigated by use of in silico and in vivo approaches...
October 12, 2017: Environmental Toxicology and Chemistry
Vikas Chandra, Dalei Wu, Sheng Li, Nalini Potluri, Youngchang Kim, Fraydoon Rastinejad
Assessing the physical connections and allosteric communications in multi-domain nuclear receptor (NR) polypeptides has remained challenging, with few crystal structures available to show their overall structural organizations. Here we report the quaternary architecture of multi-domain retinoic acid receptor β-retinoic X receptor α (RARβ-RXRα) heterodimer bound to DNA, ligands and coactivator peptides, examined through crystallographic, hydrogen-deuterium exchange mass spectrometry, mutagenesis and functional studies...
October 11, 2017: Nature Communications
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