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Bounded rationality

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https://www.readbyqxmd.com/read/28911863/the-crystal-structure-of-the-pyrococcus-abyssi-mono-functional-methyltransferase-patrm5b
#1
Jialiang Wu, Qian Jia, Saibin Wu, Hui Zeng, Yujie Sun, Caiyan Wang, Ruiguang Ge, Wei Xie
The wyosine hypermodification found exclusively at G37 of tRNA(Phe) in eukaryotes and archaea is a very complicated process involving multiple steps and enzymes, and the derivatives are essential for the maintenance of the reading frame during translation. In the archaea Pyrococcus abyssi, two key enzymes from the Trm5 family, named PaTrm5a and PaTrm5b respectively, start the process by forming N1-methylated guanosine (m(1)G37). In addition, PaTrm5a catalyzes the further methylation of C7 on 4-demethylwyosine (imG-14) to produce isowyosine (imG2) at the same position...
September 11, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28905521/covalent-assembled-monolayers-of-homo-and-heteroleptic-fe-ii-terpyridyl-complexes-on-siox-and-ito-coated-glass-substrates-an-experimental-and-theoretical-study
#2
Dr Prakash Chandra Mondal, Vikram Singh, Arun K Manna, Michael Zharnikov
Well-defined Fe(II)-terpyridyl monolayers were fabricated on SiOx and conductive ITO-coated glass substrates via covalent bond formation between the metallo-organic complexes and a pre-assembled coupling layer. Three different homo- and heteroleptic complexes with the terminal pyridyl, amine, and phenyl groups were tested. All the films were found to be densely packed, homogeneous, and consisting of upright standing molecules. They exhibited high thermal (up to ~220°C) and temporal (up to 5h at 100°C) stability...
September 14, 2017: Chemphyschem: a European Journal of Chemical Physics and Physical Chemistry
https://www.readbyqxmd.com/read/28900175/dynamic-and-kinetic-elements-of-%C3%A2%C2%B5-opioid-receptor-functional-selectivity
#3
Abhijeet Kapoor, Gerard Martinez-Rosell, Davide Provasi, Gianni de Fabritiis, Marta Filizola
While the therapeutic effect of opioids analgesics is mainly attributed to µ-opioid receptor (MOR) activation leading to G protein signaling, their side effects have mostly been linked to β-arrestin signaling. To shed light on the dynamic and kinetic elements underlying MOR functional selectivity, we carried out close to half millisecond high-throughput molecular dynamics simulations of MOR bound to a classical opioid drug (morphine) or a potent G protein-biased agonist (TRV-130). Statistical analyses of Markov state models built using this large simulation dataset combined with information theory enabled, for the first time: a) Identification of four distinct metastable regions along the activation pathway, b) Kinetic evidence of a different dynamic behavior of the receptor bound to a classical or G protein-biased opioid agonist, c) Identification of kinetically distinct conformational states to be used for the rational design of functionally selective ligands that may eventually be developed into improved drugs; d) Characterization of multiple activation/deactivation pathways of MOR, and e) Suggestion from calculated transition timescales that MOR conformational changes are not the rate-limiting step in receptor activation...
September 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28890776/discovery-of-a-potent-protein-kinase-d-inhibitor-insights-in-the-binding-mode-of-pyrazolo-3-4-d-pyrimidine-analogues
#4
Klaas Verschueren, Mathias Cobbaut, Joachim Demaerel, Lina Saadah, Arnout R D Voet, Johan Van Lint, Wim M De Borggraeve
In this study, we set out to rationally optimize PKD inhibitors based on the pyrazolo[3,4-d]pyrimidine scaffold. The lead compound for this study was 1-NM-PP1, which was previously found by us and others to inhibit PKD. In our screening we identified one compound (3-IN-PP1) displaying a 10-fold increase in potency over 1-NM-PP1, opening new possibilities for specific protein kinase inhibitors for kinases that show sensitivity towards pyrazolo[3,4-d]pyrimidine derived compounds. Interestingly the observed SAR was not in complete agreement with the commonly observed binding mode where the pyrazolo[3,4-d]pyrimidine compounds are bound in a similar fashion as PKD's natural ligand ATP...
March 1, 2017: MedChemComm
https://www.readbyqxmd.com/read/28890347/high-resolution-structure-discloses-the-potential-for-allosteric-regulation-of-mitogen-activated-protein-kinase-kinase-7
#5
Takayoshi Kinoshita, Takuma Hashimoto, Yuri Sogabe, Harumi Fukada, Takashi Matsumoto, Masaaki Sawa
Mitogen-activated protein kinase kinase 7 (MAP2K7) regulates stress and inflammatory responses, and is an attractive drug discovery target for several diseases including arthritis and cardiac hypertrophy. Intracellular proteins such as MAP2K7 are prone to aggregation due to cysteine-driven oxidation in in vitro experiments. MAP2K7 instability due to the four free cysteine residues on the molecular surface abrogated the crystal growth and led to a low-resolution structure with large residual errors. To acquire a higher resolution structure for promoting rational drug discovery, we explored stable mutants of MAP2K7 by replacing the surface cysteine residues, Cys147, Cys218, Cys276 and Cys296...
September 7, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28883156/structural-insights-into-the-interaction-of-the-nuclear-exosome-helicase-mtr4-with-the-pre-ribosomal-protein-nop53
#6
Sebastian Falk, Jan-Niklas Tants, Jerôme Basquin, Matthias Thoms, Ed Hurt, Michael Sattler, Elena Conti
The nuclear exosome and the associated RNA helicase Mtr4 participate in the processing of several ribonucleoprotein particles (RNP), including the maturation of the large ribosomal subunit (60S). S. cerevisiae Mtr4 interacts directly with Nop53, a ribosomal biogenesis factor present in late pre-60S particles containing precursors of the 5.8S rRNA. The Mtr4-Nop53 interaction plays a pivotal role in the maturation of the 5.8S rRNA, providing a physical link between the nuclear exosome and the pre-60S RNP. An analogous interaction between Mtr4 and another ribosome biogenesis factor, Utp18, directs the exosome to an earlier pre-ribosomal particle...
September 7, 2017: RNA
https://www.readbyqxmd.com/read/28882892/structural-features-of-human-inositol-phosphate-multikinase-rationalize-its-inositol-phosphate-kinase-and-phosphoinositide-3-kinase-activities
#7
Huanchen Wang, Stephen B Shears
Human inositol phosphate multikinase (HsIPMK) critically contributes to intracellular signaling through its inositol-1,4,5-trisphosphate (Ins(1,4,5)P3) 3-kinase and phosphatidylinositol- 4,5-bisphosphate (PtdIns(4,5)P2) 3-kinase activities. This catalytic profile is not conserved; orthologs from Arabidopsis thaliana and Saccharomyces cerevisiae are predominantly Ins(1,4,5)P3 6-kinases, and the plant enzyme cannot phosphorylate PtdIns(4,5)P2. Therefore, crystallographic analysis of the yeast and plant enzymes, without bound inositol phosphates, do not structurally rationalize HsIPMK activities...
September 7, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28881087/organometallic-dna-b12-conjugates-as-potential-oligonucleotide-vectors-synthesis-structural-and-binding-studies-with-human-cobalamin-transport-proteins
#8
Elena Mutti, Miriam Hunger, Sergey Fedosov, Ebba Nexo, Bernhard Kräutler
We report on the synthesis and structural characterization of Co-(dN)25-Cbl and Co-(dN)39-Cbl, organometallic DNA-B12-conjugates with single DNA-strands consisting of 25 and 39 deoxy-nucleotides, respectively, and on binding studies of these two DNA-cobalamin (DNA-Cbl) conjugates to the three homologous human Cbl transporting proteins transcobalamin (TC), intrinsic factor (IF) and haptocorrin (HC). This investigation tests the suitability of such DNA-Cbls for the task of eventual in-vivo oligonucleotide delivery...
September 7, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28879000/an-investigation-into-the-unusual-linkage-isomerization-and-nitrite-reduction-activity-of-a-novel-tris-2-pyridyl-copper-complex
#9
Isolda Roger, Claire Wilson, Hans M Senn, Stephen Sproules, Mark D Symes
The copper-containing nitrite reductases (CuNIRs) are a class of enzymes that mediate the reduction of nitrite to nitric oxide in biological systems. Metal-ligand complexes that reproduce the salient features of the active site of CuNIRs are therefore of fundamental interest, both for elucidating the possible mode of action of the enzymes and for developing biomimetic catalysts for nitrite reduction. Herein, we describe the synthesis and characterization of a new tris(2-pyridyl) copper complex ([Cu1(NO2)2]) that binds two molecules of nitrite, and displays all three of the common binding modes for [Formula: see text], with one nitrite bound in an asymmetric quasi-bidentate κ(2)-ONO manner and the other bound in a monodentate fashion with a linkage isomerism between the κ(1)-ONO and κ(1)-NO2 binding modes...
August 2017: Royal Society Open Science
https://www.readbyqxmd.com/read/28878957/control-mechanisms-for-stochastic-biochemical-systems-via-computation-of-reachable-sets
#10
Eszter Lakatos, Michael P H Stumpf
Controlling the behaviour of cells by rationally guiding molecular processes is an overarching aim of much of synthetic biology. Molecular processes, however, are notoriously noisy and frequently nonlinear. We present an approach to studying the impact of control measures on motifs of molecular interactions that addresses the problems faced in many biological systems: stochasticity, parameter uncertainty and nonlinearity. We show that our reachability analysis formalism can describe the potential behaviour of biological (naturally evolved as well as engineered) systems, and provides a set of bounds on their dynamics at the level of population statistics: for example, we can obtain the possible ranges of means and variances of mRNA and protein expression levels, even in the presence of uncertainty about model parameters...
August 2017: Royal Society Open Science
https://www.readbyqxmd.com/read/28878072/high-throughput-protein-engineering-improves-the-antigenicity-and-stability-of-soluble-hiv-1-envelope-glycoprotein-sosip-trimers
#11
Jonathan T Sullivan, Chidananda Sulli, Alberto Nilo, Anila Yasmeen, Gabriel Ozorowski, Rogier W Sanders, Andrew B Ward, P J Klasse, John P Moore, Benjamin J Doranz
Soluble envelope glycoprotein (Env) trimers (SOSIP.664 gp140) are attractive HIV-1 vaccine candidates, with structures that mimic the native membrane-bound Env spike (gp160). Since engineering trimers can be limited by the difficulty of rationally predicting beneficial mutations, here we used a more comprehensive mutagenesis approach with the goal of identifying trimer variants with improved antigenic and stability properties. We created 341 cysteine pairs at predicted points of stabilization throughout gp140, 149 proline residue substitutions at every residue of the gp41 ectodomain, and 362 space-filling residue substitutions at every hydrophobic and aromatic residue in gp140...
September 6, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28862425/btn3a1-discriminates-%C3%AE-%C3%AE-t-cell-phosphoantigens-from-nonantigenic-small-molecules-via-a-conformational-sensor-in-its-b30-2-domain
#12
Mahboob Salim, Timothy J Knowles, Alfie T Baker, Martin S Davey, Mark Jeeves, Pooja Sridhar, John Wilkie, Carrie R Willcox, Hachemi Kadri, Taher E Taher, Pierre Vantourout, Adrian Hayday, Youcef Mehellou, Fiyaz Mohammed, Benjamin E Willcox
Human Vγ9/Vδ2 T-cells detect tumor cells and microbial infections by recognizing small phosphorylated prenyl metabolites termed phosphoantigens (P-Ag). The type-1 transmembrane protein Butyrophilin 3A1 (BTN3A1) is critical to the P-Ag-mediated activation of Vγ9/Vδ2 T-cells; however, the molecular mechanisms involved in BTN3A1-mediated metabolite sensing are unclear, including how P-Ag's are discriminated from nonantigenic small molecules. Here, we utilized NMR and X-ray crystallography to probe P-Ag sensing by BTN3A1...
September 14, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28846841/charge-carriers-modulate-the-bonding-of-semiconductor-nanoparticle-dopants-as-revealed-by-time-resolved-x-ray-spectroscopy
#13
Asra Hassan, Xiaoyi Zhang, Xiaohan Liu, Clare E Rowland, Ali M Jawaid, Soma Chattopadhyay, Ahmet Gulec, Armen Shamirian, Xiaobing Zuo, Robert F Klie, Richard D Schaller, Preston T Snee
Understanding the electronic structure of doped semiconductors is essential to realize advancements in electronics and in the rational design of nanoscale devices. Reported here are the results of time-resolved X-ray absorption studies on copper-doped cadmium sulfide nanoparticles that provide an explicit description of the electronic dynamics of the dopants. The interaction of a dopant ion and an excess charge carrier is unambiguously observed via monitoring the oxidation state. The experimental data combined with DFT calculations demonstrate that dopant bonding to the host matrix is modulated by its interaction with charge carriers...
August 28, 2017: ACS Nano
https://www.readbyqxmd.com/read/28845964/array-based-rational-design-of-short-peptide-probe-derived-from-an-anti-tnt-monoclonal-antibody
#14
Mina Okochi, Masaki Muto, Kentaro Yanai, Masayoshi Tanaka, Takeshi Onodera, Jin Wang, Hiroshi Ueda, Kiyoshi Toko
Complementarity-determining regions (CDRs) are sites on the variable chains of antibodies responsible for binding to specific antigens. In this study, a short peptide probe for recognition of 2,4,6-trinitrotoluene (TNT), was identified by testing sequences derived from the CDRs of an anti-TNT monoclonal antibody. The major TNT-binding site in this antibody was identified in the heavy chain CDR3 by antigen docking simulation and confirmed by an immunoassay using a spot-synthesis based peptide array comprising amino acid sequences of six CDRs in the variable region...
August 28, 2017: ACS Combinatorial Science
https://www.readbyqxmd.com/read/28842491/conformational-state-interactions-provide-clues-to-the-pharmacochaperone-potential-of-serotonin-transporter-partial-substrates
#15
Shreyas Bhat, Peter S Hasenhuetl, Ameya Kasture, Ali El-Kasaby, Michael H Baumann, Bruce E Blough, Sonja Sucic, Walter Sandtner, Michael Freissmuth
Point mutations in SLC6 transporters cause misfolding, which can be remedied by pharmacochaperones. The serotonin transporter (SERT/SLC6A4) has a rich pharmacology including inhibitors, releasers (amphetamines, which promote the exchange mode) and more recently discovered partial substrates. We hypothesized that partial substrates trapped the transporter in one or several states of the transport cycle. This conformational trapping may also be conducive to folding. We selected napthylpropane-2-amines of the phenethylamine library (PAL) including the partial substrate PAL1045 and its congeners PAL287 and PAL1046...
August 23, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28832623/variants-of-sequence-family-b-thermococcus-kodakaraensis-dna-polymerase-with-increased-mismatch-extension-selectivity
#16
Claudia Huber, Andreas Marx
Fidelity and selectivity of DNA polymerases are critical determinants for the biology of life, as well as important tools for biotechnological applications. DNA polymerases catalyze the formation of DNA strands by adding deoxynucleotides to a primer, which is complementarily bound to a template. To ensure the integrity of the genome, DNA polymerases select the correct nucleotide and further extend the nascent DNA strand. Thus, DNA polymerase fidelity is pivotal for ensuring that cells can replicate their genome with minimal error...
2017: PloS One
https://www.readbyqxmd.com/read/28817257/cation-anion-arrangement-patterns-in-self-assembled-pd2l4-and-pd4l8-coordination-cages
#17
Guido H Clever, Philip Punt
Compounds featuring one-dimensional regular arrangements of stacked metal complexes and alternating [cation-anion]∞ sequences have raised considerable interest owing to their peculiar electronic and optical properties as well as guest inclusion capabilities. While traditional ways to realize these structural motifs rely on crystalline compounds, exclusively existing in the solid state, recent progress in the area of metal-mediated supramolecular self-assembly allows for the rational synthesis of structurally well-defined short stretches of stacked metal complexes and cation-anion arrangements...
August 17, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28809485/dispersion-and-halogen-bonding-interactions-binding-of-the-axial-conformers-of-monohalo-and-%C3%A2-trans-1-2-dihalocyclohexanes-in-enantiopure-alleno-acetylenic-cages
#18
Cornelius Gropp, Tamara Husch, Nils Trapp, Markus Reiher, François Diederich
Enantiopure alleno-acetylenic cage (AAC) receptors with a resorcin[4]arene scaffold, from which four homochiral alleno-acetylenes converge to shape a cavity closed by a four-fold OH-hydrogen-bonding array, form a highly ordered porous network in the solid state. They enable the complexation and co-crystallization of otherwise non-crystalline small molecules. This paper analyzes the axial conformers of monohalo- and (±)-trans-1,2-dihalocyclohexanes, bound in the interior cavity of the AACs, on the atomic level in the solid state and in solution, accompanied by accurate calculations...
August 15, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28805809/x-ray-structures-of-endothelin-etb-receptor-bound-to-clinical-antagonist-bosentan-and-its-analog
#19
Wataru Shihoya, Tomohiro Nishizawa, Keitaro Yamashita, Asuka Inoue, Kunio Hirata, Francois Marie Ngako Kadji, Akiko Okuta, Kazutoshi Tani, Junken Aoki, Yoshinori Fujiyoshi, Tomoko Doi, Osamu Nureki
Endothelin receptors (ETRs) have crucial roles in vascular control and are targets for drugs designed to treat circulatory-system diseases and cancer progression. The nonpeptide dual-ETR antagonist bosentan is the first oral drug approved to treat pulmonary arterial hypertension. Here we report crystal structures of human endothelin ETB receptor bound to bosentan and to the ETB-selective analog K-8794, at 3.6-Å and 2.2-Å resolution, respectively. The K-8794-bound structure reveals the detailed water-mediated hydrogen-bonding network at the transmembrane core, which could account for the weak negative allosteric modulation of ETB by Na(+) ions...
September 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28802844/structural-basis-for-cullins-and-ring-component-inhibition-targeting-e3-ubiquitin-pathway-conductors-for-cancer-therapeutics
#20
Shagufta Shafique, Waqar Ali, Sonia Kanwal, Sajid Rashid
Cullin (CUL)-RING E3 ubiquitin ligases (CRLs) are attractive therapeutic targets as they regulate diverse biological processes important for cancer cell survival by conferring substrate selectivity for ubiquitination and degradation. Given the complexity of CRL complexes, steps toward the structure-based design of small-molecule inhibitors to modulate their activity have remained elusive. In this study, we explored the structural assembly and interaction details of closely related CUL scaffolds (CUL1, CUL2, CUL3, CUL4A, CUL4B, CUL5 and CUL7) with RBX1 to screen potent small molecules against CRLs...
August 10, 2017: International Journal of Biological Macromolecules
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