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https://www.readbyqxmd.com/read/28106668/primidone-inhibits-trpm3-and-attenuates-thermal-nociception-in-vivo
#1
Ute Krügel, Isabelle Straub, Holger Beckmann, Michael Schaefer
The melastatin-related transient receptor potential channel TRPM3 is a nonselective cation channel expressed in nociceptive neurons and activated by heat. Since TRPM3-deficient mice show inflammatory thermal hyperalgesia, pharmacological inhibition of TRPM3 may exert antinociceptive properties. Fluorometric Ca influx assays and a compound library containing approved or clinically tested drugs were used to identify TRPM3 inhibitors. Biophysical properties of channel inhibition were assessed using electrophysiological methods...
January 12, 2017: Pain
https://www.readbyqxmd.com/read/28106073/high-resolution-cryo-em-structure-of-the-proteasome-in-complex-with-adp-alfx
#2
Zhanyu Ding, Zhenglin Fu, Cong Xu, Yifan Wang, Yanxing Wang, Junrui Li, Liangliang Kong, Jinhuan Chen, Na Li, Rongguang Zhang, Yao Cong
The 26S proteasome is an ATP-dependent dynamic 2.5 MDa protease that regulates numerous essential cellular functions through degradation of ubiquitinated substrates. Here we present a near-atomic-resolution cryo-EM map of the S. cerevisiae 26S proteasome in complex with ADP-AlFx. Our biochemical and structural data reveal that the proteasome-ADP-AlFx is in an activated state, displaying a distinct conformational configuration especially in the AAA-ATPase motor region. Noteworthy, this map demonstrates an asymmetric nucleotide binding pattern with four consecutive AAA-ATPase subunits bound with nucleotide...
January 20, 2017: Cell Research
https://www.readbyqxmd.com/read/28105280/glun2a-selective-pyridopyrimidinone-series-of-nmdar-positive-allosteric-modulators-with-an-improved-in-vivo-profile
#3
Elisia Villemure, Matthew Volgraf, Yu Jiang, Guosheng Wu, Cuong Q Ly, Po-Wai Yuen, Aijun Lu, Xifeng Luo, Mingcui Liu, Shun Zhang, Patrick J Lupardus, Heidi J A Wallweber, Bianca M Liederer, Gauri Deshmukh, Emile Plise, Suzanne Tay, Tzu-Ming Wang, Jesse E Hanson, David H Hackos, Kimberly Scearce-Levie, Jacob B Schwarz, Benjamin D Sellers
The N-methyl-d-aspartate receptor (NMDAR) is an ionotropic glutamate receptor, gated by the endogenous coagonists glutamate and glycine, permeable to Ca(2+) and Na(+). NMDAR dysfunction is associated with numerous neurological and psychiatric disorders, including schizophrenia, depression, and Alzheimer's disease. Recently, we have disclosed GNE-0723 (1), a GluN2A subunit-selective and brain-penetrant positive allosteric modulator (PAM) of NMDARs. This work highlights the discovery of a related pyridopyrimidinone core with distinct structure-activity relationships, despite the structural similarity to GNE-0723...
January 12, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28104837/the-role-of-dimer-asymmetry-and-protomer-dynamics-in-enzyme-catalysis
#4
Tae Hun Kim, Pedram Mehrabi, Zhong Ren, Adnan Sljoka, Christopher Ing, Alexandr Bezginov, Libin Ye, Régis Pomès, R Scott Prosser, Emil F Pai
Freeze-trapping x-ray crystallography, nuclear magnetic resonance, and computational techniques reveal the distribution of states and their interconversion rates along the reaction pathway of a bacterial homodimeric enzyme, fluoroacetate dehalogenase (FAcD). The crystal structure of apo-FAcD exhibits asymmetry around the dimer interface and cap domain, priming one protomer for substrate binding. This asymmetry is dynamically averaged through conformational exchange on a millisecond time scale. During catalysis, the protomer conformational exchange rate becomes enhanced, the empty protomer exhibits increased local disorder, and water egresses...
January 20, 2017: Science
https://www.readbyqxmd.com/read/28103785/non-peptide-crf-receptor-antagonists-allosterism-kinetics-and-translation-to-efficacy-in-human-disease
#5
Dimitri E Grigoriadis, Samuel R J Hoare
G-Protein coupled receptors (GPCRs) have been, and remain a key target of drug discovery programs for human disease. While many drugs have been developed that interact with these proteins in the simple classic manner - that is - physically blocking the cognate ligand from simply binding to its target receptor, drug discovery approaches have elucidated alternative more complex methods by which small molecules can interact with these receptors and block their function. This is most evident in the Class B GPCRs where the cognate ligands are relatively large peptides with multiple points of contact on the GPCR spanning both hydrophilic and hydrophobic domains on the same protein to elicit function...
January 10, 2017: Current Molecular Pharmacology
https://www.readbyqxmd.com/read/28103783/understanding-corticotropin-releasing-factor-receptor-crfr-activation-using-structural-models
#6
Arnau Cordomi, George Liapakis, Minos Timotheos Matsoukas
The corticotropin-releasing factor type 1 and 2 receptors (CRF1R and CRF2R) belong to the secretin-like family, also known as class B1, of G protein-coupled receptors (GPCRs). Several endogenous hormones mediate their responses through the CRF receptors, such as CRF and the urocortins. The structures for the N-terminus extracellular domain of both CRF1R and CRF2R in complex with peptidic ligands were released a few years ago and permitted the study of hormone binding to the orthosteric binding site. It was not until more recently, when the crystal structure of the transmembrane domain of human CRF1R in its inactive state bound to an allosteric antagonist became available...
January 10, 2017: Current Molecular Pharmacology
https://www.readbyqxmd.com/read/28103441/enantio-specific-allosteric-modulation-of-cannabinoid-1-receptor
#7
Robert B Laprairie, Pushkar M Kulkarni, Jeffrey R Deschamps, Melanie E M Kelly, David R Janero, Maria G Cascio, Lesley A Stevenson, Roger G Pertwee, Terry Kenakin, Eileen M Denovan-Wright, Ganesh A Thakur
The cannabinoid 1 receptor (CB1R) is one of the most widely expressed metabotropic G protein-coupled receptors in brain, and its participation in various (patho)physiological processes has made CB1R activation a viable therapeutic modality. Adverse psychotropic effects limit the clinical utility of CB1R orthosteric agonists and have promoted the search for CB1R positive allosteric modulators (PAMs) with the promise of improved drug-like pharmacology and enhanced safety over typical CB1R agonists. In this study, we describe the synthesis and in vitro and ex vivo pharmacology of the novel allosteric CB1R modulator GAT211 (racemic) and its resolved enantiomers, GAT228 (R) and GAT229 (S)...
January 19, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28100642/isoform-specific-mechanisms-of-%C3%AE-3%C3%AE-4-nicotinic-acetylcholine-receptor-modulation-by-the-prototoxin-lynx1
#8
Andrew A George, Abigail Bloy, Julie M Miwa, Jon M Lindstrom, Ronald J Lukas, Paul Whiteaker
This study investigates-for the first time to our knowledge-the existence and mechanisms of functional interactions between the endogenous mammalian prototoxin, lynx1, and α3- and β4-subunit-containing human nicotinic acetylcholine receptors (α3β4*-nAChRs). Concatenated gene constructs were used to express precisely defined α3β4*-nAChR isoforms (α3β4)2β4-, (α3β4)2α3-, (α3β4)2α5(398D)-, and (α3β4)2α5(398N)-nAChR in Xenopus oocytes. In the presence or absence of lynx1, α3β4*-nAChR agonist responses were recorded by using 2-electrode voltage clamp and single-channel electrophysiology, whereas radioimmunolabeling measured cell-surface expression...
January 18, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28099001/conformational-dynamics-in-penicillin-binding-protein-2a-of-methicillin-resistant-staphylococcus-aureus-allosteric-communication-network-and-enablement-of-catalysis
#9
Kiran V Mahasenan, Rafael Molina, Renee Bouley, Maria T Batuecas, Jed F Fisher, Juan A Hermoso, Mayland Chang, Shahriar Mobashery
The mechanism of the β-lactam antibacterials is the functionally irreversible acylation of the enzymes that catalyze the cross-linking steps in the biosynthesis of their peptidoglycan cell wall. The Gram-positive pathogen Staphylococcus aureus uses one primary resistance mechanism. An enzyme, called penicillin-binding protein 2a (PBP2a), is brought into this biosynthetic pathway to complete the cross-linking. PBP2a effectively discriminates against the β-lactam antibiotics as potential inhibitors, and in favor of the peptidoglycan substrate...
January 18, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28098230/molecular-mechanism-of-the-allosteric-regulation-of-the-%C3%AE-%C3%AE-heterodimer-of-human-nad-dependent-isocitrate-dehydrogenase
#10
Tengfei Ma, Yingjie Peng, Wei Huang, Jianping Ding
Human NAD-dependent isocitrate dehydrogenase catalyzes the decarboxylation of isocitrate (ICT) into α-ketoglutarate in the Krebs cycle. It exists as the α2βγ heterotetramer composed of the αβ and αγ heterodimers. Previously, we have demonstrated biochemically that the α2βγ heterotetramer and αγ heterodimer can be allosterically activated by citrate (CIT) and ADP. In this work, we report the crystal structures of the αγ heterodimer with the γ subunit bound without or with different activators...
January 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28098152/human-farnesyl-pyrophosphate-synthase-is-allosterically-inhibited-by-its-own-product
#11
Jaeok Park, Michal Zielinski, Alexandr Magder, Youla S Tsantrizos, Albert M Berghuis
Farnesyl pyrophosphate synthase (FPPS) is an enzyme of the mevalonate pathway and a well-established therapeutic target. Recent research has focused around a newly identified druggable pocket near the enzyme's active site. Pharmacological exploitation of this pocket is deemed promising; however, its natural biological function, if any, is yet unknown. Here we report that the product of FPPS, farnesyl pyrophosphate (FPP), can bind to this pocket and lock the enzyme in an inactive state. The Kd for this binding is 5-6 μM, within a catalytically relevant range...
January 18, 2017: Nature Communications
https://www.readbyqxmd.com/read/28097900/structure-activity-relationships-of-fraxamoside-as-an-unusual-xanthine-oxidase-inhibitor
#12
Rosa Maria Vitale, Lina Antenucci, Margherita Gavagnin, Gennaro Raimo, Pietro Amodeo
Fraxamoside, a macrocyclic secoiridoid glucoside featuring a hydroxytyrosol group, was recently identified as a xanthine oxidase inhibitor (XOI) comparable in potency in vitro to the standard antigout drug allopurinol. However, this activity and its considerably higher value than its derivatives oleuropein, oleoside 11-methyl ester, and hydroxytyrosol are not explained by structure-activity relationships (SARs) of known XOIs. To exclude allosteric mechanisms, we first determined the inhibition kinetic of fraxamoside...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
https://www.readbyqxmd.com/read/28097883/is-angiotensin-3-4-val-tyr-the-shortest-angiotensin-ii-derived-peptide-opening-new-vistas-on-the-renin-angiotensin-system
#13
Juliana Dias, Flavia Axelband, Lucienne S Lara, Humberto Muzi-Filho, Adalberto Vieyra
Angiotensin-(3-4) (Ang-(3-4) or Val-Tyr) is the shorter angiotensin (Ang) II-derived peptide, formed through successive hydrolysis that culminates with the release of Val-Tyr as a dipeptide. It is formed both in plasma and in kidney from Ang II and Ang III, and can be considered a component of the systemic and organ-based renin-angiotensin system. It is potently antihypertensive in humans and rats, and its concerted actions on proximal tubule cells culminate in the inhibition of fluid reabsorption, hyperosmotic urinary excretion of Na(+)...
January 2017: Journal of the Renin-angiotensin-aldosterone System: JRAAS
https://www.readbyqxmd.com/read/28097385/two-phase-1-dose-escalation-studies-exploring-multiple-regimens-of-litronesib-ly2523355-an-eg5-inhibitor-in-patients-with-advanced-cancer
#14
Jeffrey R Infante, Amita Patnaik, Claire F Verschraegen, Anthony J Olszanski, Montaser Shaheen, Howard A Burris, Anthony W Tolcher, Kyriakos P Papadopoulos, Muralidhar Beeram, Scott M Hynes, Jennifer Leohr, Aimee Bence Lin, Lily Q Li, Anna McGlothlin, Daphne L Farrington, Eric H Westin, Roger B Cohen
PURPOSE: This first-in-human report examined the recommended Phase 2 dose and schedule of litronesib, a selective allosteric kinesin Eg5 inhibitor. METHODS: Two concurrent dose-escalation studies investigated litronesib across the dose range of 0.125-16 mg/m(2)/day, evaluating the following schedules of administration on a 21-day cycle: Days 1, 2, 3; Days 1, 5, 9; Days 1, 8; Days 1, 5; or Days 1, 4, with or without pegfilgrastim. Best overall response was defined per Response Evaluation Criteria in Solid Tumors (RECIST Version 1...
January 17, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28096460/occupancy-of-the-zinc-binding-site-by-transition-metals-decreases-the-substrate-affinity-of-the-human-dopamine-transporter-by-an-allosteric-mechanism
#15
Yang Li, Felix P Mayer, Peter S Hasenhuetl, Verena Burtscher, Klaus Schicker, Harald H Sitte, Michael Freissmuth, Walter Sandtner
The human dopamine transporter (DAT) has a tetrahedral Zn(2+)-binding site. Zn(2+)-binding sites are also recognized by other first row transition metals. Excessive accumulation of manganese or of copper can lead to Parkinsonism due to dopamine deficiency. Accordingly, we examined the effect of Mn(2+), Co(2+), Ni(2+) and Cu(2+)on transport-associated currents through DAT and DAT-H193K, a mutant with a disrupted Zn(2+)-binding site. All transition metals - but Mn(2+) - modulated the transport cycle of wild type DAT with affinities in the low µM range...
January 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28096191/allosteric-modulation-of-the-substrate-specificity-of-acyl-coa-wax-alcohol-acyltransferase-2-awat2
#16
Jason M Arne, Made Airanthi K Widjaja-Adhi, Taylor Hughes, Kevin W Huynh, Josie A Silvaroli, Sylwia Chelstowska, Vera Y Moiseenkova-Bell, Marcin Golczak
The esterification of alcohols with fatty acids is a universal mechanism to form inert storage forms of sterols, di- and triacylglycerols, and retinoids. In ocular tissues, formation of retinyl esters is an essential step in the enzymatic regeneration of the visual chromophore (11-cis-retinal). Acyl-CoA wax alcohol acyltransferase 2 (AWAT2), also known as multifunctional O-acyltransferase (MFAT), is an integral membrane enzyme with a broad substrate specificity that has been shown to preferentially esterify 11-cis-retinol and thus contribute to formation of readily available pool of cis retinoids in the eye...
January 17, 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28096095/functional-role-and-therapeutic-targeting-of-p21-associated-kinase-4-pak4-in-multiple-myeloma
#17
Mariateresa Fulciniti, Joaquin Martinez-Lopez, William Senapedis, Stefania Oliva, Rajya Lakshmi Bandi, Nicola Amodio, Yan Xu, Raphael L Szalat, Annamaria Gulla, Mehmet K Samur, Aldo Roccaro, Maria Linares, Michele Cea, Erkan Baloglu, Christian Argueta, Yosef Landesman, Sharon Shacham, Siyuan Liu, Monica Schenone, Shiaw-Lin Wu, Barry Karger, Rao Prabhala, Kenneth C Anderson, Nikhil C Munshi
Dysregulated oncogenic serine/threonine kinases play a pathological role in diverse forms of malignancies, including multiple myeloma (MM), and thus represent potential therapeutic targets. Here, we evaluated the biological and functional role of p21-activated kinase 4 (PAK4), and its potential as a new target in MM for clinical applications. PAK4 promoted MM cell growth and survival via activation of MM survival signaling pathways, including the MEK-ERK pathway. Furthermore, treatment with orally bioavailable PAK4 allosteric modulator (KPT-9274) significantly impacted MM cell growth and survival in a large panel of MM cell lines and primary MM cells alone and in the presence of bone marrow microenvironment...
January 17, 2017: Blood
https://www.readbyqxmd.com/read/28095404/entropy-transfer-between-residue-pairs-and-allostery-in-proteins-quantifying-allosteric-communication-in-ubiquitin
#18
Aysima Hacisuleyman, Burak Erman
It has recently been proposed by Gunasakaran et al. that allostery may be an intrinsic property of all proteins. Here, we develop a computational method that can determine and quantify allosteric activity in any given protein. Based on Schreiber's transfer entropy formulation, our approach leads to an information transfer landscape for the protein that shows the presence of entropy sinks and sources and explains how pairs of residues communicate with each other using entropy transfer. The model can identify the residues that drive the fluctuations of others...
January 17, 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28095400/computational-analysis-of-residue-interaction-networks-and-coevolutionary-relationships-in-the-hsp70-chaperones-a-community-hopping-model-of-allosteric-regulation-and-communication
#19
Gabrielle Stetz, Gennady M Verkhivker
Allosteric interactions in the Hsp70 proteins are linked with their regulatory mechanisms and cellular functions. Despite significant progress in structural and functional characterization of the Hsp70 proteins fundamental questions concerning modularity of the allosteric interaction networks and hierarchy of signaling pathways in the Hsp70 chaperones remained largely unexplored and poorly understood. In this work, we proposed an integrated computational strategy that combined atomistic and coarse-grained simulations with coevolutionary analysis and network modeling of the residue interactions...
January 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28094924/reversible-and-selective-encapsulation-of-dextromethorphan-and-%C3%AE-estradiol-using-an-asymmetric-molecular-capsule-assembled-via-the-weak-link-approach
#20
Jose Mendez-Arroyo, Andrea I d'Aquino, Alyssa B Chinen, Yashin D Manraj, Chad A Mirkin
An allosterically regulated, asymmetric receptor featuring a binding cavity large enough to accommodate three-dimensional pharmaceutical guest molecules as opposed to planar, rigid aromatics, was synthesized via the Weak-Link Approach. This architecture is capable of switching between an expanded, flexible "open" configuration and a collapsed, rigid "closed" one. The structure of the molecular receptor can be completely modulated in situ through the use of simple ionic effectors, which reversibly control the coordination state of the Pt(II) metal hinges to open and close the molecular receptor...
January 17, 2017: Journal of the American Chemical Society
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