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Molecular receptor affinity

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https://www.readbyqxmd.com/read/28223697/dynamic-regulation-of-gdp-binding-to-g-proteins-revealed-by-magnetic-field-dependent-nmr-relaxation-analyses
#1
Yuki Toyama, Hanaho Kano, Yoko Mase, Mariko Yokogawa, Masanori Osawa, Ichio Shimada
Heterotrimeric guanine-nucleotide-binding proteins (G proteins) serve as molecular switches in signalling pathways, by coupling the activation of cell surface receptors to intracellular responses. Mutations in the G protein α-subunit (Gα) that accelerate guanosine diphosphate (GDP) dissociation cause hyperactivation of the downstream effector proteins, leading to oncogenesis. However, the structural mechanism of the accelerated GDP dissociation has remained unclear. Here, we use magnetic field-dependent nuclear magnetic resonance relaxation analyses to investigate the structural and dynamic properties of GDP bound Gα on a microsecond timescale...
February 22, 2017: Nature Communications
https://www.readbyqxmd.com/read/28221352/dynamic-undocking-and-the-quasi-bound-state-as-tools-for-drug-discovery
#2
Sergio Ruiz-Carmona, Peter Schmidtke, F Javier Luque, Lisa Baker, Natalia Matassova, Ben Davis, Stephen Roughley, James Murray, Rod Hubbard, Xavier Barril
There is a pressing need for new technologies that improve the efficacy and efficiency of drug discovery. Structure-based methods have contributed towards this goal but they focus on predicting the binding affinity of protein-ligand complexes, which is notoriously difficult. We adopt an alternative approach that evaluates structural, rather than thermodynamic, stability. As bioactive molecules present a static binding mode, we devised dynamic undocking (DUck), a fast computational method to calculate the work necessary to reach a quasi-bound state at which the ligand has just broken the most important native contact with the receptor...
March 2017: Nature Chemistry
https://www.readbyqxmd.com/read/28220785/c-edge-loops-of-arrestin-function-as-a-membrane-anchor
#3
Ciara C M Lally, Brian Bauer, Jana Selent, Martha E Sommer
G-protein-coupled receptors are membrane proteins that are regulated by a small family of arrestin proteins. During formation of the arrestin-receptor complex, arrestin first interacts with the phosphorylated receptor C terminus in a pre-complex, which activates arrestin for tight receptor binding. Currently, little is known about the structure of the pre-complex and its transition to a high-affinity complex. Here we present molecular dynamics simulations and site-directed fluorescence experiments on arrestin-1 interactions with rhodopsin, showing that loops within the C-edge of arrestin function as a membrane anchor...
February 21, 2017: Nature Communications
https://www.readbyqxmd.com/read/28220706/human-cannabinoid-receptor-2-ligand-interaction-motif-transmembrane-helix-2-cysteine-c2-59-89-as-determinant-of-classical-cannabinoid-agonist-activity-and-binding-pose
#4
Han Zhou, Yan Peng, Aneetha Halikhedkar, Pusheng Fan, David R Janero, Ganesh A Thakur, Richard Warren Mercier, Xin Sun, Xiaoyu Ma, Alexandros Makriyannis
Cannabinoid receptor 2 (CB2R)-dependent signaling is implicated in neuronal physiology and immune surveillance by brain microglia. Selective CB2R agonists hold therapeutic promise for inflammatory and other neurological disorders. Information on human CB2R (hCB2R) ligand-binding and functional domains is needed to inform the rational design and optimization of candidate drug-like hCB2R agonists. Prior demonstration that hCB2R transmembrane helix 2 (TMH2) cysteine C2.59(89) reacts with small-molecule methanethiosulfonates showed that this cysteine residue is accessible to sulfhydryl derivatization reagents...
February 21, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28219245/real-time-analysis-of-binding-events-between-different-a%C3%AE-1-42-species-and-human-lilrb2-by-dual-polarization-interferometry
#5
Tao Hu, Shuang Wang, Chuanxia Chen, Jian Sun, Xiurong Yang
Abnormal accumulation of 42-residue amyloid-β (Aβ1-42) within the brain triggers the pathogenesis of Alzheimer's disease (AD). In this paper, we use a dual polarization interferometry (DPI) tool to evaluate the binding events of various Aβ1-42 species such as monomeric Aβ1-42, low molecular weight Aβ1-42 oligomer (LMW Aβ1-42), and high molecular weight Aβ1-42 oligomer (HMW Aβ1-42) with extracellular D1D2 domain of lilrb2 (ED1D2L) receptor that has been proved to be associated with AD. Based on the real-time binding information provided by DPI, the association rate (ka) of ED1D2L receptor with monomeric Aβ1-42, LMW Aβ1-42, and HMW Aβ1-42 is individually determined to be 2...
February 21, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28218686/natural-products-as-chemopreventive-agents-by-potential-inhibition-of-the-kinase-domain-in-erbb-receptors
#6
Maria Olivero-Acosta, Wilson Maldonado-Rojas, Jesus Olivero-Verbel
Small molecules found in natural products provide therapeutic benefits due to their pharmacological or biological activity, which may increase or decrease the expression of human epidermal growth factor receptor (HER), a promising target in the modification of signaling cascades involved in excessive cellular growth. In this study, in silico molecular protein-ligand docking protocols were performed with AutoDock Vina in order to evaluate the interaction of 800 natural compounds (NPs) from the NatProd Collection (http://www...
February 17, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28216098/potential-influences-of-complement-factor-h-in-autoimmune-inflammatory-and-thrombotic-disorders
#7
Janez Ferluga, Lubna Kouser, Valarmathy Murugaiah, Robert B Sim, Uday Kishore
Complement system homeostasis is important for host self-protection and anti-microbial immune surveillance, and recent research indicates roles in tissue development and remodelling. Complement also appears to have several points of interaction with the blood coagulation system. Deficiency and altered function due to gene mutations and polymorphisms in complement effectors and regulators, including Factor H, have been associated with familial and sporadic autoimmune inflammatory - thrombotic disorders, in which autoantibodies play a part...
February 16, 2017: Molecular Immunology
https://www.readbyqxmd.com/read/28216000/pharmacological-and-molecular-characterization-of-the-positive-allosteric-modulators-of-metabotropic-glutamate-receptor-2
#8
REVIEW
L Lundström, C Bissantz, J Beck, M Dellenbach, T J Woltering, J Wichmann, S Gatti
The metabotropic glutamate receptor 2 (mGlu2) plays an important role in the presynaptic control of glutamate release and several mGlu2 positive allosteric modulators (PAMs) have been under assessment for their potential as antipsychotics. The binding mode of mGlu2 PAMs is better characterized in functional terms while few data are available on the relationship between allosteric and orthosteric binding sites. Pharmacological studies characterizing binding and effects of two different chemical series of mGlu2 PAMs are therefore carried out here using the radiolabeled mGlu2 agonist (3)[H]-LY354740 and mGlu2 PAM (3)[H]-2,2,2-TEMPS...
February 16, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28215671/dual-ligand-%C3%AE-5%C3%AE-1-and-%C3%AE-6%C3%AE-4-integrin-targeting-enhances-gene-delivery-and-selectivity-to-cancer-cells
#9
Rachel M Levine, Efrosini Kokkoli
Nanoparticles functionalized with cancer-targeting ligands have shown promise but are still limited by off-tumor binding to healthy tissues that express low levels of the molecular target. Targeting two cancer biomarkers using dual-targeted heteromultivalent nanoparticles presents a possible solution to this challenge by requiring overexpression of two separate ligands for localization. In order to guide experimental design, a kinetic model was built to explore how the affinity and valency of dual-ligand liposomes affect the binding and selectivity of delivery to cells with various receptor expression...
February 16, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/28213834/molecular-simulation-of-receptor-occupancy-and-tumor-penetration-of-an-antibody-and-smaller-scaffolds-application-to-molecular-imaging
#10
Kelly D Orcutt, Gregory P Adams, Anna M Wu, Matthew D Silva, Catey Harwell, Jack Hoppin, Manabu Matsumura, Masakatsu Kotsuma, Jonathan Greenberg, Andrew M Scott, Robert A Beckman
PURPOSE: Competitive radiolabeled antibody imaging can determine the unlabeled intact antibody dose that fully blocks target binding but may be confounded by heterogeneous tumor penetration. We evaluated the hypothesis that smaller radiolabeled constructs can be used to more accurately evaluate tumor expressed receptors. PROCEDURES: The Krogh cylinder distributed model, including bivalent binding and variable intervessel distances, simulated distribution of smaller constructs in the presence of increasing doses of labeled antibody forms...
February 17, 2017: Molecular Imaging and Biology: MIB: the Official Publication of the Academy of Molecular Imaging
https://www.readbyqxmd.com/read/28212459/structural-studies-of-nicotinoids-cotinine-vs-nicotine
#11
Iciar Uriarte, Cristóbal Pérez, Elena Caballero-Mancebo, Francisco J Basterretxea, Alberto Lesarri, José A Fernández, Emilio J Cocinero
Nicotinoids are agonists of the acetylcholine receptor (nAChR) and play important biochemical and pharmacological roles. Here we report on the structural and conformational landscape of cotinine, and compare its molecular properties with the nicotine prototype, from which it only differs in the addition of a carbonyl group. The investigation of cotinine included a theoretical survey of the effects of rotamerization of the pyridine moiety, the puckering of the pyrrolidinone ring and the internal rotation of the methyl group...
February 17, 2017: Chemistry: a European Journal
https://www.readbyqxmd.com/read/28211669/3-aminomethyl-derivatives-of-2-phenylimidazo-1-2-a-pyridine-as-positive-allosteric-modulators-of-gabaa-receptor-with-potential-antipsychotic-activity
#12
Monika Marcinkowska, Marcin Kolaczkowski, Krzysztof Kamiński, Adam Bucki, Maciej Henryk Pawlowski, Agata Siwek, Tadeusz Karcz, Gabriela Starowicz, Karolina Sloczynska, Elżbieta Pękala, Anna Wesołowska, Jerzy Samochowiec, Paweł Mierzejewski, Przemyslaw Bienkowski
Schizophrenia is a mental illness characterized by behavioral changes as well as anatomical and neurochemical abnormalities. There has been a remarkable progress in the drug discovery for schizophrenia; however, antipsychotics that act through molecular targets, other than monoaminergic receptors, have not been developed. One of the hypotheses of schizophrenia states that GABAergic dysfunction might be implemented in the pathophysiology of this disease. Our recent findings and previous clinical observations have suggested that modulation of GABAergic system through α1-GABAA receptors would represent an original approach for the treatment of schizophrenia...
February 17, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28211013/electrostatic-forces-as-dominant-interactions-between-proteins-and-polyanions-an-esi-ms-study-of-fibroblast-growth-factor-binding-to-heparin-oligomers
#13
Burcu Baykal Minsky, Paul L Dubin, Igor A Kaltashov
The interactions between fibroblast growth factors (FGFs) and their receptors (FGFRs) are facilitated by heparan sulfate (HS) and heparin (Hp), highly sulfated biological polyelectrolytes. The molecular basis of FGF interactions with these polyelectrolytes is highly complex due to the structural heterogeneity of HS/Hp, and many details still remain elusive, especially the significance of charge density and minimal chain length of HS/Hp in growth factor recognition and multimerization. In this work, we use electrospray ionization mass spectrometry (ESI MS) to investigate the association of relatively homogeneous oligoheparins (octamer, dp8, and decamer, dp10) with acidic fibroblast growth factor (FGF-1)...
February 16, 2017: Journal of the American Society for Mass Spectrometry
https://www.readbyqxmd.com/read/28198086/calcium-independent-activation-of-an-allosteric-network-in-langerin-by-heparin-oligosaccharides
#14
Jonas Hanske, Robert Wawrzinek, Andreas Geissner, Eike-Christian Wamhoff, Katrin Sellrie, Henrik Schmidt, Peter H Seeberger, Christoph Rademacher
The C-type lectin receptor Langerin is a glycan binding protein that serves as an uptake receptor on Langerhans cells and is essential for the formation of Birbeck granules. Whereas most of Langerin´s ligands are recognized via a canonical Ca2+-dependent binding site, interactions with heparins have been proposed to make additional contacts to a secondary, Ca2+-independent site. Glycan array screening and biomolecular NMR spectroscopy were employed to investigate the molecular mechanism of these interactions...
February 14, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28197404/using-global-analysis-to-extend-the-accuracy-and-precision-of-binding-measurements-with-t-cell-receptors-and-their-peptide-mhc-ligands
#15
Sydney J Blevins, Brian M Baker
In cellular immunity, clonally distributed T cell receptors (TCRs) engage complexes of peptides bound to major histocompatibility complex proteins (pMHCs). In the interactions of TCRs with pMHCs, regions of restricted and variable diversity align in a structurally complex fashion. Many studies have used mutagenesis to attempt to understand the "roles" played by various interface components in determining TCR recognition properties such as specificity and cross-reactivity. However, these measurements are often complicated or even compromised by the weak affinities TCRs maintain toward pMHC...
2017: Frontiers in Molecular Biosciences
https://www.readbyqxmd.com/read/28197324/-125-i-f56-peptide-as-radioanalysis-agent-targeting-vegfr1-in-mice-xenografted-with-human-gastric-tumor
#16
Hua Zhu, Chuanke Zhao, Fei Liu, Lixin Wang, Junnan Feng, Chengchao Shou, Zhi Yang
(125)I-Radiolabeled F56 peptide was designed as a radioactive analogue of F56 (peptide WHSDMEWWYLLG) to bind with VEGFR1 receptor. It was synthesized in high radiochemical yield and specific activity. The in vitro stability of (125)I-F56 was tested, and the bioactivity of (125)I-F56 was confirmed by both cell uptake and binding affinity measurement in VEGFR1 positive BGC-823 cells. The time-radioactivity relationship and biodistribution of (125)I-F56 tracer were conducted using nude mice bearing human gastric carcinoma BGC-823, by noninvasive micro-SPECT/CT imaging...
February 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28195200/dynamical-footprint-of-cross-reactivity-in-a-human-autoimmune-t-cell-receptor
#17
Amit Kumar, Francesco Delogu
The present work focuses on the dynamical aspects of cross-reactivity between myelin based protein (MBP) self-peptide and two microbial peptides (UL15, PMM) for Hy.1B11 T-cell receptor (TCR). This same TCR was isolated from a patient suffering from multiple sclerosis (MS). The study aims at highlighting the chemical interactions underlying recognition mechanisms between TCR and the peptides presented by Major Histocompatibility Complex (MHC) proteins, which form a crucial component in adaptive immune response against foreign antigens...
February 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28193552/rational-design-and-synthesis-of-some-ppar-%C3%AE-agonists-substituted-benzylideneamino-benzylidene-thiazolidine-2-4-diones
#18
Santosh S Chhajed, Shital Chaskar, Sanjay K Kshirsagar, G M Animeshchandra Haldar, Debarshi Kar Mahapatra
The peroxisome proliferator activator receptor-γ (PPAR-γ) remained the most successful target for management of diabetes mellitus. The present work endeavors rational designing of some novel PPAR-γ agonists bearing benzylideneamino-benzylidene-thiazolidine-2,4-dione scaffold. The research involved virtual screening of 37 different molecules by molecular docking studies performed by Molecular Design Suite (MDS) into the ligand binding domain of PPAR-γ receptor to explore the binding affinity and conformations of the molecules...
February 7, 2017: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/28193459/epileptiform-activity-and-behavioral-arrests-in-mice-overexpressing-the-calcium-channel-subunit-%C3%AE-2%C3%AE-1
#19
Leonardo C Faria, Feng Gu, Isabel Parada, Ben Barres, Z David Luo, David A Prince
: The alpha2delta-1 subunit (α2δ-1) of voltage-gated calcium channels is a receptor for astrocyte-secreted thrombospondins that promote developmental synaptogenesis.Alpha2delta-1 receptors are upregulated in models of injury-induced peripheral pain and epileptogenic neocortical trauma associated with an enhancement of excitatory synaptic connectivity. These results lead to the hypothesis that overexpression of α2δ-1 alone in neocortex of uninjured transgenic (TG) mice might result in increased excitatory connectivity and consequent cortical hyperexcitability and epileptiform activity...
February 10, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28187351/identifying-binding-modes-of-two-synthetic-derivatives-of-adrenalin-to-the-%C3%AE-2c-adrenoceptor-by-using-molecular-modeling-insights-into-the-%C3%AE-2c-adrenoceptor-activation
#20
Samira Gholami, A Khalegh Bordbar, Amir Lohrasebi
Although, α2C adrenergic receptor (AR) mediates a number of physiological functions in vivo and has great therapeutic potential, the absence of its crystal structure is a major difficulty in the activation mechanism studies and drug design endeavors. Here, a homology model of α2C AR has been presented by means of multiple sequence alignment. The used templates were the latest crystal structures of the other ARs (Protein Data Bank IDs: 2R4R, 2RH1, 4GPO, 3P0G, 4BVN and 4LDO) that have 38.4% identity with the query...
February 2, 2017: Biophysical Chemistry
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