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https://www.readbyqxmd.com/read/27914066/computational-tools-for-allosteric-drug-discovery-site-identification-and-focus-library-design
#1
Wenkang Huang, Ruth Nussinov, Jian Zhang
Allostery is an intrinsic phenomenon of biological macromolecules involving regulation and/or signal transduction induced by a ligand binding to an allosteric site distinct from a molecule's active site. Allosteric drugs are currently receiving increased attention in drug discovery because drugs that target allosteric sites can provide important advantages over the corresponding orthosteric drugs including specific subtype selectivity within receptor families. Consequently, targeting allosteric sites, instead of orthosteric sites, can reduce drug-related side effects and toxicity...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27913116/multiple-conformations-of-gal3-protein-drive-the-galactose-induced-allosteric-activation-of-the-gal-genetic-switch-of-saccharomyces-cerevisiae
#2
Rajesh Kumar Kar, Hungyo Kharerin, Ranjith Padinhateeri, Paike Jayadeva Bhat
Gal3p is an allosteric monomeric protein which activates the GAL genetic switch of Saccharomyces cerevisiae in response to galactose. Expression of constitutive mutant of Gal3p or overexpression of wild-type Gal3p activates the GAL switch in the absence of galactose. These data suggest that Gal3p exists as an ensemble of active and inactive conformations. Structural data has indicated that Gal3p exists in open (inactive) and closed (active) conformations. However, mutant of Gal3p that predominantly exists in inactive conformation and yet capable of responding to galactose has not been isolated...
November 29, 2016: Journal of Molecular Biology
https://www.readbyqxmd.com/read/27911811/the-structure-of-the-catechin-binding-site-of-human-sulfotransferase-1a1
#3
Ian Cook, Ting Wang, Mark Girvin, Thomas S Leyh
We are just beginning to understand the allosteric regulation of the human cytosolic sulfotransferase (SULTs) family-13 disease-relevant enzymes that regulate the activities of hundreds, if not thousands, of signaling small molecules. SULT1A1, the predominant isoform in adult liver, harbors two noninteracting allosteric sites, each of which binds a different molecular family: the catechins (naturally occurring flavonols) and nonsteroidal antiinflammatory drugs (NSAIDs). Here, we present the structure of an SULT allosteric binding site-the catechin-binding site of SULT1A1 bound to epigallocatechin gallate (EGCG)...
November 23, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27910743/decoding-the-polyphyletic-flexibility-of-allosteric-modular-networks-progress-and-perspectives
#4
Yanan Yu, Zhong Wang, Yongyan Wang
Advances in identifying architecture of modules and elucidating their modes of action are gradually improving the decoding of complex relationships between phenotypic robustness and genotypic networks. However, approaches to detecting modules have largely focused on identifying modules in static graphs. In this review, we attempt to reveal the mechanism of polyphyletic architectural transformation based on modular boundary evolutions and different oscillating factors. With the rapid progress in probing into the detailed structural model of modular networks, flexible modular organization manifests a key adaptive balancing ability of allosterically regulating or reconstructing intermodular and intramodular states to uncover the novel biological alterations beyond engineering properties...
2016: Critical Reviews in Eukaryotic Gene Expression
https://www.readbyqxmd.com/read/27908764/discovery-and-initial-optimization-of-alkoxyanthranilic-acid-derivatives-as-inhibitors-of-hcv-ns5b-polymerase
#5
Kyle Parcella, Andrew Nickel, Brett R Beno, Steven Sheriff, Changhong Wan, Ying-Kai Wang, Susan B Roberts, Nicholas A Meanwell, John F Kadow
Alkoxyanthranilic acid derivatives have been identified to inhibit HCV NS5B polymerase, binding in an allosteric site located at the convergence of the palm and thumb regions. Information from co-crystal structures guided the structural design strategy. Ultimately, two independent structural modifications led to a similar shift in binding mode that when combined led to a synergistic improvement in potency and the identification of inhibitors with sub-micromolar HCV NS5B binding potency.
November 22, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27908761/discovery-of-dual-positive-allosteric-modulators-pams-of-the-metabotropic-glutamate-2-receptor-and-cyslt1-antagonists-for-treating-migraine-headache
#6
Maria-Jesus Blanco, Dana R Benesh, James A Knobelsdorf, Albert Khilevich, Guillermo S Cortez, Fese Mokube, Thomas D Aicher, Todd M Groendyke, Fredrik P Marmsater, Tony P Tang, Kirk W Johnson, Amy Clemens-Smith, Mark A Muhlhauser, Steven Swanson, John Catlow, Renee Emkey, Michael P Johnson, Jeffrey M Schkeryantz
Pyridylmethylsulfonamide series were the first reported example of positive allosteric modulators (PAM) of the mGlu2 receptor. The hydroxyacetophenone scaffold is a second series of mGlu2 PAMs we have identified. This series of molecules are potent mGlu2 potentiators and possess significant CysLT1 (cysteinyl leukotriene receptor 1) antagonist activity, showing in vivo efficacy in a dural plasma protein extravasation (PPE) model of migraine. In this paper, we describe the dual SAR, pharmacokinetics and preclinical in vivo efficacy data for a tetrazole containing hydroxyacetophenone scaffold...
November 18, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27908269/levamisole-a-positive-allosteric-modulator-for-the-%C3%AE-3%C3%AE-4-nicotinic-acetylcholine-receptors-prevents-weight-gain-in-cd-1-mice-on-a-high-fat-diet
#7
Jeanne A Lewis, Jerrel L Yakel, Anshul A Pandya
Neuronal nicotinic acetylcholine receptors (nAChRs) regulate the function of multiple neurotransmitter pathways throughout the central nervous system. This includes nAChRs found on the proopiomelanocortin neurons in the hypothalamus. Activation of these nAChRs by nicotine causes a decrease in consumption of food in rodents. In this study, we tested the effect of subtype selective allosteric modulators for nAChRs on the body weight of CD-1 mice. Levamisole, an allosteric modulator for the α3β4 subtype of nAChRs, prevented weight gain in mice that were fed a high fat diet...
December 1, 2016: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/27905440/organization-and-functions-of-mglu-and-gabab-receptor-complexes
#8
Jean-Philippe Pin, Bernhard Bettler
The neurotransmitters glutamate and γ-aminobutyric acid (GABA) transmit synaptic signals by activating fast-acting ligand-gated ion channels and more slowly acting G-protein-coupled receptors (GPCRs). The GPCRs for these neurotransmitters, metabotropic glutamate (mGlu) and GABAB receptors, are atypical GPCRs with a large extracellular domain and a mandatory dimeric structure. Recent studies have revealed how these receptors are activated through multiple allosteric interactions between subunit domains. It emerges that the molecular complexity of these receptors is further increased through association with trafficking, effector and regulatory proteins...
December 1, 2016: Nature
https://www.readbyqxmd.com/read/27903755/homobivalent-conjugation-increases-the-allosteric-effect-of-9-aminoacridine-at-the-%C3%AE-1-adrenergic-receptors
#9
Adrian P Campbell, Laurence P G Wakelin, William A Denny, Angela M Finch
The α1 adrenergic receptors are targets for a number of cardiovascular and CNS conditions, however current drugs for these receptors lack specificity to be of optimal clinical value. Allosteric modulators offer an alternative mechanism of action to traditional α1 adrenergic ligands, yet there is little information describing this drug class at the α1 adrenergic receptors. We have identified a series of 9-aminoacridine compounds that demonstrate allosteric modulation of the α1A and α1B adrenergic receptors...
November 30, 2016: Molecular Pharmacology
https://www.readbyqxmd.com/read/27899437/allosteric-control-of-antibody-prion-recognition-through-oxidation-of-a-disulfide-bond-between-the-ch-and-cl-chains
#10
Jun Zhao, Ruth Nussinov, Buyong Ma
Molecular details of the recognition of disordered antigens by their cognate antibodies have not been studied as extensively as folded protein antigens and much is still unknown. To follow the conformational changes in the antibody and cross-talk between its subunits and with antigens, we performed molecular dynamics (MD) simulations of the complex of Fab and prion-associated peptide in the apo and bound forms. We observed that the inter-chain disulfide bond in constant domains restrains the conformational changes of Fab, especially the loops in the CH1 domain, resulting in inhibition of the cross-talk between Fab subdomains that thereby may prevent prion peptide binding...
November 29, 2016: Protein Engineering, Design & Selection: PEDS
https://www.readbyqxmd.com/read/27899324/understanding-the-common-themes-and-diverse-roles-of-the-second-extracellular-loop-ecl2-of-the-gpcr-super-family
#11
Michael J Woolley, Alex C Conner
The extracellular loops (ECLs) of G protein-coupled receptors (GPCRs) can bind directly to docked orthosteric or allosteric ligands, they can contain transient contact points for ligand entry into the transmembrane (TM) bundle and they can regulate the activation of the receptor signalling pathways. Of the three ECLs, ECL2 is the largest and most structurally diverse reflecting its functional importance. This has been shown through biochemical techniques and has been supported by the many subsequent crystal structures of GPCRs bound to both agonists and antagonists...
November 26, 2016: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/27898710/identification-of-a-novel-inhibitory-allosteric-site-in-p38%C3%AE
#12
Patricia Gomez-Gutierrez, Pedro M Campos, Miguel Vega, Juan J Perez
In the present study, we report the discovery of a novel allosteric inhibitory site for p38α, a subclass of the mitogen-activated protein kinases (MAPK) family. The putative site was discovered after inspection of the crystallographic structure of the p38α-MK2 complex. MK2 (MAPK-activated protein kinase 2) is an interesting protein playing a dual role as modulator and substrate of p38α. This intriguing behavior is due to the ability of the two proteins to form distinctive heterodimers when p38α is phosphorylated or not...
2016: PloS One
https://www.readbyqxmd.com/read/27897972/mechanism-of-allosteric-regulation-of-%C3%AE-2-adrenergic-receptor-by-cholesterol
#13
Moutusi Manna, Miia Niemelä, Joona Tynkkynen, Matti Javanainen, Waldemar Kulig, Daniel J Müller, Tomasz Rog, Ilpo Vattulainen
There is evidence that lipids can be allosteric regulators of membrane protein structure and activation. However, there are no data showing how exactly the regulation emerges from specific lipid-protein interactions. Here we show in atomistic detail how the human β2-adrenergic receptor (β2AR) - a prototypical G protein-coupled receptor - is modulated by cholesterol in an allosteric fashion. Extensive atomistic simulations show that cholesterol regulates β2AR by limiting its conformational variability. The mechanism of action is based on the binding of cholesterol at specific high-affinity sites located near the transmembrane helices 5-7 of the receptor...
November 29, 2016: ELife
https://www.readbyqxmd.com/read/27896809/a2a-d2-receptor-receptor-interaction-modulates-gliotransmitter-release-from-striatal-astrocyte-processes
#14
Chiara Cervetto, Arianna Venturini, Mario Passalacqua, Diego Guidolin, Susanna Genedani, Kjell Fuxe, Dasiel O Borroto-Esquela, Pietro Cortelli, Amina Woods, Guido Maura, Manuela Marcoli, Luigi F Agnati
Evidence for striatal A2A-D2 heterodimers has led to a new perspective on molecular mechanisms involved in schizophrenia and Parkinson's disease. Despite the increasing recognition of astrocytes' participation in neuropsychiatric disease vulnerability, involvement of striatal astrocytes in A2A and D2 receptor signal transmission has never been explored. Here, we investigated the presence of D2 and A2A receptors in isolated astrocyte processes prepared from adult rat striatum by confocal imaging; the effects of receptor activation were measured on the 4-aminopyridine-evoked release of glutamate from the processes...
November 5, 2016: Journal of Neurochemistry
https://www.readbyqxmd.com/read/27893848/the-open-form-inducer-approach-for-structure-based-drug-design
#15
Daniel Ken Inaoka, Maiko Iida, Toshiyuki Tabuchi, Teruki Honma, Nayoung Lee, Satoshi Hashimoto, Shigeru Matsuoka, Takefumi Kuranaga, Kazuhito Sato, Tomoo Shiba, Kimitoshi Sakamoto, Emmanuel Oluwadare Balogun, Shigeo Suzuki, Takeshi Nara, Josmar Rodrigues da Rocha, Carlos Alberto Montanari, Akiko Tanaka, Masayuki Inoue, Kiyoshi Kita, Shigeharu Harada
Many open form (OF) structures of drug targets were obtained a posteriori by analysis of co-crystals with inhibitors. Therefore, obtaining the OF structure of a drug target a priori will accelerate development of potent inhibitors. In addition to its small active site, Trypanosoma cruzi dihydroorotate dehydrogenase (TcDHODH) is fully functional in its monomeric form, making drug design approaches targeting the active site and protein-protein interactions unrealistic. Therefore, a novel a priori approach was developed to determination the TcDHODH active site in OF...
2016: PloS One
https://www.readbyqxmd.com/read/27891077/presynaptic-g-protein-coupled-receptors-gatekeepers-of-addiction
#16
REVIEW
Kari A Johnson, David M Lovinger
Drug abuse and addiction cause widespread social and public health problems, and the neurobiology underlying drug actions and drug use and abuse is an area of intensive research. Drugs of abuse alter synaptic transmission, and these actions contribute to acute intoxication as well as the chronic effects of abused substances. Transmission at most mammalian synapses involves neurotransmitter activation of two receptor subtypes, ligand-gated ion channels that mediate fast synaptic responses and G protein-coupled receptors (GPCRs) that have slower neuromodulatory actions...
2016: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/27890928/identification-and-characterization-of-activating-abl1-1b-kinase-mutations-impact-on-sensitivity-to-atp-competitive-and-allosteric-abl1-inhibitors
#17
B J Lee, N P Shah
While pathologically activated ABL1 fusion kinases represent well-validated therapeutic targets, tumor genomic sequencing has identified numerous point mutations in the ABL1 proto-oncogene of unclear significance. Here we describe nine novel ABL1 1b point mutations, including two from clinical isolates, that cause constitutive kinase activation and cellular transformation. All mutants retained sensitivity to ATP-competitive tyrosine kinase inhibitors (TKIs). Several substitutions cluster near the myristoyl-binding pocket, the target of ABL001, a novel clinically active allosteric kinase inhibitor that mimics the autoinhibitory myristoyl group, and likely activate the kinase by relieving physiologic autoinhibition...
November 28, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27890920/protein-export-through-the-bacterial-sec-pathway
#18
Alexandra Tsirigotaki, Jozefien De Geyter, Nikolina Šoštaric, Anastassios Economou, Spyridoula Karamanou
The general secretory (Sec) pathway comprises an essential, ubiquitous and universal export machinery for most proteins that integrate into, or translocate through, the plasma membrane. Sec exportome polypeptides are synthesized as pre-proteins that have cleavable signal peptides fused to the exported mature domains. Recent advances have re-evaluated the interaction networks of pre-proteins with chaperones that are involved in pre-protein targeting from the ribosome to the SecYEG channel and have identified conformational signals as checkpoints for high-fidelity targeting and translocation...
November 28, 2016: Nature Reviews. Microbiology
https://www.readbyqxmd.com/read/27890784/identifying-residues-that-determine-scf-molecular-level-interactions-through-a-combination-of-experimental-and-in-silico-analyses
#19
Eitan Rabinovich, Michael Heyne, Anna Bakhman, Mickey Kosloff, Julia M Shifman, Niv Papo
The stem cell factor (SCF)/c-Kit receptor tyrosine kinase complex - with its significant roles in hematopoiesis and angiogenesis - is an attractive target for rational drug design. There is thus a need to map, in detail, the SCF/c-Kit interaction sites and the mechanisms that modulate this interaction. While most residues in the direct SCF/c-Kit binding interface can be identified from the existing crystal structure of the complex, other residues that affect binding through protein unfolding, intermolecular interactions, or allosteric or long-distance electrostatic effects cannot be directly inferred...
November 24, 2016: Journal of Molecular Biology
https://www.readbyqxmd.com/read/27889489/the-drug-candidate-adx71441-is-a-novel-potent-and-selective-positive-allosteric-modulator-of-the-gabab-receptor-with-a-potential-for-treatment-of-anxiety-pain-and-spasticity
#20
Mikhail Kalinichev, Françoise Girard, Hasnaà Haddouk, Mélanie Rouillier, Eric Riguet, Isabelle Royer-Urios, Vincent Mutel, Robert Lütjens, Sonia Poli
Positive allosteric modulation of the GABAB receptor is a promising alternative to direct activation of the receptor as a therapeutic approach for treatment of addiction, chronic pain, anxiety, epilepsy, autism, Fragile X syndrome, and psychosis. Here we describe in vitro and in vivo characterization of a novel, potent and selective GABAB positive allosteric modulator (PAM) N-(5-(4-(4-chloro-3-fluorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide (ADX71441). In vitro, Schild plot and reversibility tests at the target confirmed PAM properties of the compound...
November 23, 2016: Neuropharmacology
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