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Kumju Youn, Ji-Hyun Park, Seonah Lee, Seungeun Lee, Jinhyuk Lee, Eun-Young Yun, Woo-Sik Jeong, Mira Jun
β-site amyloid precursor protein cleaving enzyme 1 (BACE1) plays a role in generating amyloid β (Aβ), thus playing a major part early in the pathogenesis of Alzheimer's disease (AD). BACE1 has emerged as a crucial therapeutic target for decreasing the Aβ concentration in the AD brain. To explore natural BACE1 inhibitors, the present study concentrated on isoflavones, including genistein, formononetin, glycitein, daidzein, and puerarin. In this study, in vitro anti-AD activities were assessed using BACE1 inhibition assays, as well as enzyme kinetic predictions...
February 14, 2018: Journal of Medicinal Food
Madoka Akimoto, Bryan VanSchouwen, Giuseppe Melacini
The hyperpolarization-activated cyclic-nucleotide-gated (HCN) ion channels control nerve impulse transmission and cardiac pacemaker activity. The modulation by cAMP is critical for the regulatory function of HCN in both neurons and cardiomyocytes, but the underlying mechanism is not fully understood. Here, we show how the structure of the apo cAMP-binding domain of the HCN4 isoform has contributed to a model for the cAMP-dependent modulation of the HCN ion-channel. This model recapitulates the structural and dynamical changes that occur along the thermodynamic cycle arising from the coupling of cAMP-binding and HCN self-association equilibria...
February 14, 2018: FEBS Journal
Mathivanan Chinnaraj, Zhiwei Chen, Leslie A Pelc, Zachary Grese, Dominika Bystranowska, Enrico Di Cera, Nicola Pozzi
The clotting factor prothrombin exists in equilibrium between closed and open conformations, but the physiological role of these forms remains unclear. As for other allosteric proteins, elucidation of the linkage between molecular transitions and function is facilitated by reagents stabilized in each of the alternative conformations. The open form of prothrombin has been characterized structurally, but little is known about the architecture of the closed form that predominates in solution under physiological conditions...
February 13, 2018: Scientific Reports
Min Ju Park, Hailian Shen, Jason M Spaeth, Jaana H Tolvanen, Courtney Failor, Jennifer F Knudtson, Jessica McLaughlin, Sunil K Halder, Qiwei Yang, Serdar E Bulun, Ayman Al-Hendy, Robert S Schenken, Lauri A Aaltonen, Thomas G Boyer
Somatic mutations in exon 2 of the RNA polymerase II transcriptional Mediator subunit MED12 occur at high frequency in uterine fibroids (UFs) and breast fibroepithelial tumors as well as recurrently, albeit less frequently, in malignant uterine leimyosarcomas, chronic lymphocytic leukemias, and colorectal cancers. Previously, we reported that UF-linked mutations in MED12 disrupt its ability to activate CycC-dependent kinase 8 (CDK8), implicating impaired Mediator-associated CDK8 activity in the pathogenesis of these clinically significant lesions...
February 13, 2018: Journal of Biological Chemistry
Allison Germann, Daniel Shin, Christina Kuhrau, Alexander Johnson, Alex S Evers, Gustav Akk
GABAA receptors activated by the transmitter GABA are potentiated by several allosterically acting drugs including the intravenous anesthetic propofol. Propofol can also directly activate the receptor, albeit at higher concentrations. Previous functional studies have identified amino acid residues whose substitution reduces potentiation of GABA-activated receptors by propofol while enhancing the ability of propofol to directly activate the receptor. One interpretation of such observations is that the mutation has specific effects on the sites or processes involved in potentiation or activation...
February 8, 2018: Molecular Pharmacology
Ron Zhi-Hui Chiang, Samuel Ken-En Gan, Chinh Tran-To Su
HIV drug resistant mutations that render the current Highly Active Anti-Retroviral Therapy cocktail drugs ineffective are increasingly reported. To study the mechanisms of these mutations in conferring drug resistance, we computationally analyzed fourteen Reverse Transcriptase (RT) structures of HIV-1 on the following parameters: drug-binding pocket volume, allosteric effects caused by the mutations, and structural thermal stability. We constructed structural correlation-based networks of the mutant RT-drug complexes and the analyses support the use of Efavirenz as the first-line drug, given that cross-resistance is least likely to develop from Efavirenz-resistant mutations...
February 5, 2018: Bioscience Reports
Shigeki Kiyonaka, Seiji Sakamoto, Sho Wakayama, Yuma Morikawa, Muneo Tsujikawa, Itaru Hamachi
AMPA-type glutamate receptors (AMPARs) mediate fast excitatory synaptic transmission in the central nervous system. Disregulation of AMPAR function is associated with many kinds of neurological, neurodegenerative and psychiatric disorders. As a result, molecules capable of controlling AMPAR functions are potential therapeutic agents. Fluorescent semisynthetic biosensors have attracted considerable interest for the discovery of ligands selectively acting on target proteins. Given the large protein complex formation of AMPARs in live cells, biosensors using full-length AMPARs retaining original functionality are ideal for drug screening...
February 13, 2018: ACS Chemical Biology
Rui Chen, Jiehua Xu, Yanling She, Ting Jiang, Shanyao Zhou, Huacai Shi, Cheng Li
Necrostatin-1 (Nec-1) is a selective and potent allosteric inhibitor of necroptosis by specifically inhibiting the activity of receptor‑interacting protein (RIP) 1 kinase. The aim of the present study was to determine the effect of Nec‑1 on an anoxia model comprising mouse skeletal C2C12 myotubes. In the present study, a hypoxic mimetic reagent, cobalt chloride (CoCl2), was used to induce hypoxia in C2C12 myotubes. The cytotoxic effects of CoCl2‑induced hypoxia were determined by a Cell Counting kit‑8 assay and flow cytometry...
February 6, 2018: International Journal of Molecular Medicine
Blaine Jacobs, Miryam M Pando, Elaine M Jennings, Teresa S Chavera, William P Clarke, Kelly A Berg
There is abundant evidence for formation of G protein coupled receptor heteromers in heterologous expression systems, however, little is known of the function of heteromers in native systems. Heteromers of delta and kappa opioid receptors (DOR-KOR heteromers) have been identified in native systems. We previously reported that activation of DOR-KOR heteromers expressed by rat pain-sensing neurons (nociceptors) produces robust, peripherally-mediated antinociception. Moreover, DOR agonist potency and efficacy is regulated by KOR antagonists via allosteric interactions within the DOR-KOR heteromer in a ligand-dependent manner...
February 7, 2018: Molecular Pharmacology
Xiao Yu, Nicholas P Franks, William Wisden
Sedatives target just a handful of receptors and ion channels. But we have no satisfying explanation for how activating these receptors produces sedation. In particular, do sedatives act at restricted brain locations and circuitries or more widely? Two prominent sedative drugs in clinical use are zolpidem, a GABA A receptor positive allosteric modulator, and dexmedetomidine (DEX), a selective α2 adrenergic receptor agonist. By targeting hypothalamic neuromodulatory systems both drugs induce a sleep-like state, but in different ways: zolpidem primarily reduces the latency to NREM sleep, and is a controlled substance taken by many people to help them sleep; DEX produces prominent slow wave activity in the electroencephalogram (EEG) resembling stage 2 NREM sleep, but with complications of hypothermia and lowered blood pressure-it is used for long term sedation in hospital intensive care units-under DEX-induced sedation patients are arousable and responsive, and this drug reduces the risk of delirium...
2018: Frontiers in Neural Circuits
Takashi Nakaoku, Takashi Kohno, Mitsugu Araki, Seiji Niho, Rakhee Chauhan, Phillip P Knowles, Katsuya Tsuchihara, Shingo Matsumoto, Yoko Shimada, Sachiyo Mimaki, Genichiro Ishii, Hitoshi Ichikawa, Satoru Nagatoishi, Kouhei Tsumoto, Yasushi Okuno, Kiyotaka Yoh, Neil Q McDonald, Koichi Goto
Resistance to vandetanib, a type I RET kinase inhibitor, developed in a patient with metastatic lung adenocarcinoma harboring a CCDC6-RET fusion that initially exhibited a response to treatment. The resistant tumor acquired a secondary mutation resulting in a serine-to-phenylalanine substitution at codon 904 in the activation loop of the RET kinase domain. The S904F mutation confers resistance to vandetanib by increasing the ATP affinity and autophosphorylation activity of RET kinase. A reduced interaction with the drug is also observed in vitro for the S904F mutant by thermal shift assay...
February 12, 2018: Nature Communications
Marcus Thelen, Daniel F Legler
Migration of leukocytes is typically mediated by G protein-coupled receptors (GPCRs) upon activation by specific ligands that range from small peptides, chemokines to a variety of lipidic molecules. The heptahelical receptors are highly dynamic structures and the signaling efficiency largely depends on the discrete contact with the ligand. In addition, several allosteric modulators of receptor activity have been reported, which do not induce migration by themselves. Another important mechanism modulating the activity of GPCRs is their local environment...
February 9, 2018: Cytokine
Hugo Lavoie, Malha Sahmi, Pierre Maisonneuve, Sara A Marullo, Neroshan Thevakumaran, Ting Jin, Igor Kurinov, Frank Sicheri, Marc Therrien
RAF family kinases have prominent roles in cancer. Their activation is dependent on dimerization of their kinase domains, which has emerged as a hindrance for drug development. In mammals, RAF family kinases include three catalytically competent enzymes (ARAF, BRAF and CRAF) and two pseudokinases (KSR1 and KSR2) that have been described as scaffolds owing to their apparent ability to bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK). Kinase suppressor of Ras (KSR) pseudokinases were also shown to dimerize with kinase-competent RAFs to stimulate catalysis allosterically...
February 12, 2018: Nature
Alyne Alexandrino Antunes, Larissa de Oliveira Passos Jesus, Marcella Araújo Manfredi, Aline Aparecida de Souza, Maurício Ferreira Marcondes Machado, Pamela Moraes E Silva, Marcelo Yudi Icimoto, Maria Aparecida Juliano, Luiz Juliano, Wagner Alves de Souza Judice
Kex2 is the prototype of a large family of eukaryotic subtilisin-related proprotein-processing proteases that cleave at sites containing pairs of basic residues. Here, we studied the effects of KCl on the individual rate constants of association, dissociation, acylation and deacylation and determined the thermodynamic parameters at each step of the Kex2 reaction. Potassium bound Kex2 with KD=20.3mM. The order in which potassium entered the reaction system modified the effect of activation or inhibition, which depended on the size of the substrate...
December 5, 2017: Biophysical Chemistry
Tian-Min Fu, Chen Shen, Qiubai Li, Pengfei Zhang, Hao Wu
Tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) plays a vital role in immune signal transduction pathways by acting as a ubiquitin ligase (E3) for Lys63-linked polyubiquitin chain synthesis. However, the detailed mechanism by which the TRAF6 RING dimer promotes ubiquitin transfer was unknown. Through structural modeling and biochemical analysis, we here show that the TRAF6 RING dimer employs a concerted allosteric mechanism using both subunits of the TRAF6 dimer to promote ubiquitin (Ub) transfer...
February 5, 2018: Proceedings of the National Academy of Sciences of the United States of America
Gabrielle Stetz, Gennady M Verkhivker
A fundamental role of the Hsp90-Cdc37 chaperone machinery in mediating conformational development and activation of diverse protein kinase clients is essential for signal transduction. Structural and biochemical studies have demonstrated that characterization of global conformational changes and allosteric interactions in the Hsp90-Cdc37-kinase complexes are central to our understanding of the mechanisms underlying kinase recruitment and processing by the Hsp90-Cdc37 chaperone. The recent cryo-electron microscopy structure of the Hsp90-Cdc37-Cdk4 kinase complex has provided a framework for dissecting regulatory principles underlying differentiation and recruitment of protein kinase clients to the chaperone machinery...
February 12, 2018: Journal of Chemical Information and Modeling
Clifford Thomas Gee, Keith E Arntson, Edward J Koleski, Rachel Lynn Staebell, William Charles Krause Pomerantz
Protein-Observed Fluorine NMR Spectroscopy (PrOF NMR) is an emerging technique for screening and characterizing small molecule-protein interactions. The choice of which amino acid to label for PrOF NMR can be critical for analysis. Here we report the first use of a protein containing two different fluoroaromatic amino acids for NMR studies. Using the KIX domain of the CBP/p300 as a model system, we examine ligand binding of several small molecules elaborated from our previous fragment screen and identify a new ligand binding site distinct from those used by native transcription factors...
February 11, 2018: Chembiochem: a European Journal of Chemical Biology
Maryam Abdullahi, Fisayo A Olotu, Mahmoud E Soliman
Lymphocyte Function Associated antigen-1(LFA-1) has been implicated severely in the pathophysiology of inflammatory and autoimmune diseases. Its active and inactive conformations correlate with its diseased and non-diseased state respectively. This is determined by its degree of affinity for its intrinsic ligand (ICAM) at the active site and accompanying synergistic coordination at the α7 helix. This potentiates the role of inhibitors in disrupting this interaction allosterically. Herein, we present a first account of the structural dynamics which characterizes the inhibitory effect of a novel LFA-1 antagonist, Lifitegrast (SAR1118), upon binding to the I-domain allosteric site (IDAS) using molecular dynamics simulation...
February 5, 2018: Computational Biology and Chemistry
Lars Eng, Brandon L Garcia, Brian V Geisbrecht, Anders Hanning
Surface plasmon resonance (SPR) is a well-established method for biomolecular interaction studies. SPR monitors the binding of molecules to a solid surface, embodied as refractive index changes close to the surface. One limitation of conventional SPR is the universal nature of the detection that results in an inability to qualitatively discriminate between different binding species. Furthermore, it is impossible to directly discriminate two species simultaneously binding to different sites on a protein, which limits the utility of SPR, for example, in the study of allosteric binders or bi-specific molecules...
February 7, 2018: Biochemical and Biophysical Research Communications
Min Zhong, Eric Peng, Ningwu Huang, Qi Huang, Anja Huq, Meiyen Lau, Richard Colonno, Leping Li
This letter describes the discovery of a fused benzofuran scaffold viable for preparing a series of novel potent HCV NS5B polymerase non-nucleoside inhibitors. Designed on the basis of the functionalized benzofuran derivative nesbuvir (HCV-796), these compounds presumably bind similarly to the allosteric binding site in the "palm" domain of HCV NS5B protein. SAR of each potential hydrogen-bonding interaction site of this novel scaffold is discussed along with some preliminary genotypic profile and PK data of several advanced compounds...
January 31, 2018: Bioorganic & Medicinal Chemistry Letters
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