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Bounded rationality

Zhimei Li, Yiyuan Zhang, Lixia Chen, Hua Li
Overexpression of the prosurvival protein BCL-2 contributes to malignant cell initiation, progression and resistance to treatment. Agents that function as its natural antagonists targeting BCL-2 must provide therapeutic benefit. In SW1990 pancreatic cancer cells, amplified BCL-2 was observed, which was believed to offer advantages for malignant cell survival and lead to poor patient outcome. Using structure-based virtual ligand screening, luteolin was found to be a natural small-molecule inhibitor of BCL-2, which exhibited dose-response proapoptosis activity in a BCL-2 dependent manner in vitro...
May 17, 2018: Food & Function
Marie S Prevost, Gabriel Waksman
Human infections by the intracellular bacterial pathogen Legionella pneumophila result in a severe form of pneumonia, the Legionnaire's disease. L. pneumophila utilises a type IVb secretion (T4bS) system termed "dot/icm" to secrete protein effectors to the host cytoplasm. The dot/icm system is powered at least in part by a functionally critical AAA+ ATPase, a protein called DotB, thought to belong to the VirB11 family of proteins. Here we present the crystal structure of DotB at 3.19 Å resolution, in its hexameric form...
May 17, 2018: Protein Science: a Publication of the Protein Society
Tomonori Tamura, Tsuyoshi Ueda, Taiki Goto, Taku Tsukidate, Yonatan Shapira, Yuki Nishikawa, Alma Fujisawa, Itaru Hamachi
Selective modification of native proteins in live cells is one of the central challenges in recent chemical biology. As a unique bioorthogonal approach, ligand-directed chemistry recently emerged, but the slow kinetics limits its scope. Here we successfully overcome this obstacle using N-acyl-N-alkyl sulfonamide as a reactive group. Quantitative kinetic analyses reveal that ligand-directed N-acyl-N-alkyl sulfonamide chemistry allows for rapid modification of a lysine residue proximal to the ligand binding site of a target protein, with a rate constant of ~104  M-1  s-1 , comparable to the fastest bioorthogonal chemistry...
May 14, 2018: Nature Communications
Gustavo P B Carretero, Greice K V Saraiva, Ana C G Cauz, Magali A Rodrigues, Sumika Kiyota, Karin A Riske, Alcindo A Dos Santos, Marcos F Pinatto-Botelho, Marcelo P Bemquerer, Frederico J Gueiros-Filho, Hernan Chaimovich, Shirley Schreier, Iolanda M Cuccovia
Antimicrobial peptides (AMPs) work as a primary defense against pathogenic microorganisms. BP100, (KKLFKKILKYL-NH2 ), a rationally designed short, highly cationic AMP, acts against many bacteria, displaying low toxicity to eukaryotic cells. Previously we found that its mechanism of action depends on membrane surface charge and on peptide-to-lipid ratio. Here we present the synthesis of two BP100 analogs: BP100‑alanyl‑hexadecyl‑1‑amine (BP100-Ala-NH-C16 H33 ) and cyclo(1‑4)‑d‑Cys1 , Ile2 , Leu3 , Cys4 -BP100 (Cyclo(1‑4)‑cILC-BP100)...
May 8, 2018: Biochimica et Biophysica Acta
Matthias Schwarz, Firas Faisal, Susanne Mohr, Chantal Hohner, Kristin Werner, Tao Xu, Tomáš Skála, Nataliya Tsud, Kevin Charles Prince, Vladimír Matolín, Yaroslava Lykhach, Jörg Libuda
Understanding the correlation between structure and reactivity of oxide surfaces is vital for the rational design of catalytic materials. In this work, we demonstrate the exceptional degree of structure sensitivity of the water dissociation reaction for one of the most important materials in catalysis and electrocatalysis. We have studied H2 O on two atomically-defined cobalt oxide surfaces, CoO(100) and Co3 O4 (111). Both surfaces are terminated by O2- and Co2+ in different coordination. By infrared reflection absorption spectroscopy and synchrotron radiation photoelectron spectroscopy we show that H2 O adsorbs molecularly on CoO(100), while it dissociates and forms very strongly bound OH and partially dissociated (H2 O)n (OH)m clusters on Co3 O4 (111)...
May 9, 2018: Journal of Physical Chemistry Letters
Shashi Thutupalli, Delphine Geyer, Rajesh Singh, Ronojoy Adhikari, Howard A Stone
Active particles, including swimming microorganisms, autophoretic colloids, and droplets, are known to self-organize into ordered structures at fluid-solid boundaries. The entrainment of particles in the attractive parts of their spontaneous flows has been postulated as a possible mechanism underlying this phenomenon. Here, combining experiments, theory, and numerical simulations, we demonstrate the validity of this flow-induced ordering mechanism in a suspension of active emulsion droplets. We show that the mechanism can be controlled, with a variety of resultant ordered structures, by simply altering hydrodynamic boundary conditions...
May 7, 2018: Proceedings of the National Academy of Sciences of the United States of America
Hui Liu, Zhuoming Li, Lang Li
Polycomb CBX proteins regulate gene expression by targeting Polycomb repressive complex 1 (PRC1) to sites of H3K27me3 via their chromodomains, which plays a key role in the development of numerous cancers. UNC3866, is a recently reported peptide-based inhibitor of the methyllysine (Kme) reading function of CBX chromodomains (CBX2, 4 and 6-8). The previous experiments showed that UNC3866 bound the chromodomains of CBX7 strongly, with ∼20-fold selectivity over other CBX chromodomains. However, the potential mechanism of UNC3866 preferentially binding to CBX7 is still unknown...
April 10, 2018: Computational Biology and Chemistry
Hoangdung Ho, Anh Miu, Mary Kate Alexander, Natalie K Garcia, Angela Oh, Inna Zilberleyb, Mike Reichelt, Cary D Austin, Christine Tam, Stephanie Shriver, Huiyong Hu, Sharada S Labadie, Jun Liang, Lan Wang, Jian Wang, Yan Lu, Hans E Purkey, John Quinn, Yvonne Franke, Kevin Clark, Maureen H Beresini, Man-Wah Tan, Benjamin D Sellers, Till Maurer, Michael F T Koehler, Aaron T Wecksler, James R Kiefer, Vishal Verma, Yiming Xu, Mireille Nishiyama, Jian Payandeh, Christopher M Koth
The movement of core-lipopolysaccharide across the inner membrane of Gram-negative bacteria is catalysed by an essential ATP-binding cassette transporter, MsbA. Recent structures of MsbA and related transporters have provided insights into the molecular basis of active lipid transport; however, structural information about their pharmacological modulation remains limited. Here we report the 2.9 Å resolution structure of MsbA in complex with G907, a selective small-molecule antagonist with bactericidal activity, revealing an unprecedented mechanism of ABC transporter inhibition...
May 2, 2018: Nature
Tanja Küssau, Marion Flipo, Niel Van Wyk, Albertus Viljoen, Vincent Olieric, Laurent Kremer, Mickaël Blaise
In mycobacteria, the ketoacyl-acyl carrier protein (ACP) reductase MabA (designated FabG in other bacteria) catalyzes the NADPH-dependent reduction of β-ketoacyl-ACP substrates to β-hydroxyacyl-ACP products. This first reductive step in the fatty-acid biosynthesis elongation cycle is essential for bacteria, which makes MabA/FabG an interesting drug target. To date, however, very few molecules targeting FabG have been discovered and MabA remains the only enzyme of the mycobacterial type II fatty-acid synthase that lacks specific inhibitors...
May 1, 2018: Acta Crystallographica. Section D, Structural Biology
Dhruvitkumar S Sutaria, Bartolome Moya, Kari B Green, Tae Hwan Kim, Xun Tao, Yuanyuan Jiao, Arnold Louie, George L Drusano, Jürgen B Bulitta
Penicillin-binding proteins (PBPs) are the high affinity target sites of all β-lactam antibiotics in bacteria. It is well known that each β-lactam covalently binds to and thereby inactivates different PBPs with varying affinity. Despite β-lactams serving as cornerstone of our therapeutic armamentarium against Klebsiella pneumoniae , PBP binding data are missing for this pathogen. We aimed to generate the first PBP binding data on 13 chemically diverse and clinically relevant β-lactams and β-lactamase inhibitors in K...
April 30, 2018: Antimicrobial Agents and Chemotherapy
Qian Yang, Jinhua Li, Xiaoyan Wang, Hailong Peng, Hua Xiong, Lingxin Chen
One pressing concern today is to construct sensors that can withstand various disturbances for highly selective and sensitive detecting trace analytes in complicated samples. Molecularly imprinted polymers (MIPs) with tailor-made binding sites are preferred to be recognition elements in sensors for effective targets detection, and fluorescence measurement assists in highly sensitive detection and user-friendly control. Accordingly, molecular imprinting-based fluorescence sensors (MI-FL sensors) have attracted great research interest in many fields such as chemical and biological analysis...
April 17, 2018: Biosensors & Bioelectronics
Ali Rohman, Niels van Oosterwijk, Ni Nyoman Tri Puspaningsih, Bauke W Dijkstra
Complete degradation of the xylan backbone of hemicellulosic plant cell walls requires the synergistic action of endo-xylanases and β-1,4-xylosidases. While endo-xylanases produce xylooligosaccharides from xylan, β-1,4-xylosidases degrade the xylooligosaccharides into xylose monomers. The glycoside hydrolase family 43 β-1,4-xylosidase from Geobacillus thermoleovorans IT-08 is a promising, heat stable catalyst for the saccharification of hemicellulosic material into simple fermentable sugars, but it is competitively inhibited by its products arabinose and xylose...
2018: PloS One
Lorena Tremiño, Alicia Forcada-Nadal, Vicente Rubio
Vitamin B6 -dependent genetic epilepsy was recently associated to mutations in PLPBP (previously PROSC), the human version of the widespread COG0325 gene that encodes TIM-barrel-like pyridoxal phosphate (PLP)-containing proteins of unclear function. We produced recombinantly, purified and characterized human PROSC (called now PLPHP) and its six missense mutants reported in epileptic patients. Normal PLPHP is largely a monomer with PLP bound through a Schiff-base linkage. The PLP-targeting antibiotic D-cycloserine decreased the PLP-bound peak as expected for pseudo-first-order reaction...
April 24, 2018: Human Mutation
Yejiao Shi, Ran Lin, Honggang Cui, Helena S Azevedo
Peptide amphiphiles (PAs), consisting of a hydrophobic alkyl chain covalently bound to a hydrophilic peptide sequence, possess a versatile molecular design due to their combined self-assembling features of amphiphile surfactants and biological functionalities of peptides. Through rational design, PAs can self-assemble into a variety of nanostructures with controlled shape, size, and biological functionality to deliver therapeutic and imaging agents to target cells. Here, we describe principles to design multifunctional PAs for self-assembly into micellar nanostructures and targeted intracellular delivery...
2018: Methods in Molecular Biology
Jianbin Zheng, Long Chen, Owen S Skinner, Daniel Ysselstein, Jonathan Remis, Peter Lansbury, Renato Skerlj, Michael Mrosek, Ursula Heunisch, Stephan Krapp, Joel Charrow, Michael Schwake, Neil L Kelleher, Richard B Silverman, Dimitri Krainc
β-Glucocerebrosidase (GCase) mutations cause Gaucher's disease and are a high risk factor in Parkinson's disease. The implementation of a small molecule modulator is a strategy to restore proper folding and lysosome delivery of degradation-prone mutant GCase. Here, we present a potent quinazoline modulator, JZ-4109, which stabilizes wild-type and N370S mutant GCase and increases GCase abundance in patient-derived fibroblast cells. We then developed a covalent modification strategy using a lysine targeted inactivator (JZ-5029) for in vitro mechanistic studies...
April 20, 2018: Journal of the American Chemical Society
Xiao Han, Renhua Sun, Tatyana Sandalova, Adnane Achour
Spr1654 from Streptococcus pneumoniae plays a key role in the production of unusual sugars, presumably functioning as a pyridoxal-5'-phosphate (PLP)-dependent aminotransferase. Spr1654 was predicted to catalyse the transferring of amino group to form the amino sugar 2-acetamido-4-amino-2, 4, 6-trideoxygalactose moiety (AATGal), representing a crucial step in biosynthesis of teichoic acids in S. pneumoniae We have determined the crystal structures of the apo-, PLP- and PMP-bound forms of Spr1654. Spr1654 forms a homodimer, in which each monomer contains one active site...
April 2018: Open Biology
Jeong Yun Kim, Heather J Kulik
We present a detailed study of nearly 70 Zn molecular catalysts for CO2 hydration from four diverse ligand classes ranging from well-studied carbonic anhydrase mimics (e.g., cyclen) to new structures we obtain by leveraging diverse hits from large organic libraries. Using kinetic analysis and establishing linear free energy relationships, we confirm turnover to be sensitive to relative thermodynamic stability of reactive hydroxyl and bound bicarbonate moieties. We observe a wide range of thermodynamic stabilities for these intermediates, showing up to 6 kcal/mol improvement over well-studied cyclen catalysts...
April 17, 2018: Journal of Physical Chemistry. A
Bjørn Hofmann, Michal Stanak
OBJECTIVES: Nudging is the purposeful alteration of choices presented to people that aims to make them choose in predicted ways. While nudging has been used to assure high uptake and good outcome of screening programs, it has been criticized for being paternalistic, undermining free choice, and shared decision making. Accordingly, the objective of this study is to explore a) nudging strategies identified in screening, b) arguments for and against nudging; and on basis of this, to c) suggest a tentative conclusion on how to handle nudging in screening...
March 27, 2018: Patient Education and Counseling
Zhendong Qin, V Sarath Babu, Ningqiu Li, Tairan Fu, Jinquan Li, Lizhu Yi, Lijuan Zhao, Jun Li, Yang Zhou, Li Lin
The emergence of multi antibiotic resistance by the pathogens and toxic impacts on host metabolism has opened new perspectives to rational novel vaccine techniques. Outbreaks of Aeromonas hydrophila in aquaculture caused high mortality throughout the world and resulted in the extensive economic loss in the aquaculture industry. In this study, we report the efficacy of anti-A. hydrophila IgY antibodies by passive vaccination and its prophylactic or therapeutic effects against A. hydrophila in blunt snout bream...
April 2, 2018: Fish & Shellfish Immunology
Michele Vitali, Valentina Rigamonti, Antonino Natalello, Barbara Colzani, Svetlana Avvakumova, Stefania Brocca, Carlo Santambrogio, Joanna Narkiewicz, Giuseppe Legname, Miriam Colombo, Davide Prosperi, Rita Grandori
BACKGROUND: Protein-nanoparticle (NP) interactions dictate properties of nanoconjugates relevant for bionanotechnology. Non-covalent adsorption generates a protein corona (PC) formed by an inner and an outer layer, the hard and soft corona (HC, SC). Intrinsically disordered proteins (IDPs) exist in solution as conformational ensembles, whose features in the presence of NPs are not well known. METHODS: Three IDPs (α-casein, Sic1 and α-synuclein) and lysozyme are compared, describing conformational properties inside HC on silica NPs by circular dichroism (CD) and Fourier-transform infrared (FTIR) spectroscopy...
April 2, 2018: Biochimica et Biophysica Acta
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