Search

PurposeThis study sets out to empirically investigate the effect of salesforce output control on perceived job autonomy, customer-oriented selling behaviours and sales performance.Design/methodology/approachData are gathered from 704 salespeople and their visiting customers in Ghana. The hypotheses are tested using the structural equations modelling technique (SEM).FindingsAccording to the findings of the study, output control has a significant and positive impact on perceived job autonomy. It also discovers that perceived job autonomy improves both customer-directed problem solving and adaptive selling behaviours. Furthermore, the study finds that customer-directed problem solving and adaptive selling behaviours both improve sales performance. Moreover, the study uncovers that perceived job autonomy mediates the relationship between output control and customer-oriented selling behaviours, whereas both customer-oriented selling behaviours mediate the relationship between perceived job autonomy and sales performance.Practical implicationsThe current study provides both practical and theoretical insights into salesforce control dynamics, job autonomy, adaptive selling behaviour, customer-directed problem-solving behaviour and sales performance. The findings have important implications for sales organisations because they can assist sales managers in determining the best type of salesforce control systems to deploy and highlight the strategic role job autonomy plays in enhancing sales performance.Originality/valueThe current study shows how output control can influence salespeople's perceived job autonomy, adaptive selling and customer-directed problem-solving behaviours, and how these can improve sales performance.

This study revealed that the synthesis of effective flow modifiers using diamine monomers and fatty acid reduces the melt viscosity of polyamide 66 (PA66) composites. Moreover, the study provided insights into the rheological and mechanical properties of these reinforced polymers. In particular, the oligomers hexamethylenediamide, dodecamethylene diamide, 4,4′-methylenebis(cyclohexylamide) (i.e., HMDA, DMDA, MCHA) to modify the PA66 were prepared from hexamethylenediamine, dodecamethylene diamine, 4,4′-methylenebis(cyclohexylamine). The synthesized modifiers showed thermal stability in the PA66 processing temperature. Further, the chemical similarity increased due to amide bonds in the backbone of the flow modifiers, showing good compatibility with PA66. Additionally, PA66/glass fiber (GF) composites containing the flow modifier showed enhanced rheological and mechanical properties. The flow modifiers significantly improved the tensile strength and flexural modulus of the PA66/GF composites. The proposed synthetic method is straightforward, opening up a new strategy for reducing the melt viscosity of PA66 without degradation of the mechanical properties. The method improves the compatibility of the PA66/GF composites even in high amounts of GF, achieving effective polymer processing for practical applications.

Orexin receptors are a family of G protein-coupled receptors that consist of two subtypes: orexin-1 receptors (OX1Rs) and OX2Rs. They are expressed throughout the central nervous system and are involved in regulating the sleep-wake cycle. The development of antagonists to orexin receptors has become important in drug discovery because modulation of these receptors can lead to novel treatments for diseases related to the regulation of sleep and wakefulness, such as insomnia. In this study, we determined that the structure of OX2R bound to lemborexant, a dual orexin receptor antagonist (DORA), at 2.89 Å resolution. Comparisons of kinetic and dynamic properties of DORAs based on structures and simulations suggest that the enthalpy of molecular binding to receptors and the entropy derived from intramolecular structure can be separately controlled. These results complement existing structural information and allow us to discuss the usefulness of pharmacophore models and target selectivity to OXRs.

Understanding and controlling protein motion at atomic resolution is a hallmark challenge for structural biologists and protein engineers because conformational dynamics are essential for complex functions such as enzyme catalysis and allosteric regulation. Time-resolved crystallography offers a window into protein motions, yet without a universal perturbation to trigger conformational changes the method has been limited in scope. Here we couple a solvent-based temperature jump with time-resolved crystallography to visualize structural motions in lysozyme, a dynamic enzyme. We observed widespread atomic vibrations on the nanosecond timescale, which evolve on the sub-millisecond timescale into localized structural fluctuations that are coupled to the active site. An orthogonal perturbation to the enzyme, inhibitor binding, altered these dynamics by blocking key motions that allow energy to dissipate from vibrations into functional movements linked to the catalytic cycle. Because temperature-jump is a universal method for perturbing molecular motion, the method demonstrated here is broadly applicable for studying protein dynamics.

Many drugs target the serotonin 2A receptor (5-HT2AR), including second-generation antipsychotics that also target the dopamine D2 receptor (D2R). These drugs often produce severe side effects due to non-selective binding to other aminergic receptors. Here, we report the structures of human 5-HT2AR in complex with the second-generation antipsychotics risperidone and zotepine. These antipsychotics effectively stabilize the inactive conformation by forming direct contacts with the residues at the bottom of the ligand-binding pocket, the movements of which are important for receptor activation. 5-HT2AR is structurally similar to 5-HT2CR but possesses a unique side-extended cavity near the orthosteric binding site. A docking study and mutagenic studies suggest that a highly 5-HT2AR-selective antagonist binds the side-extended cavity. The conformation of the ligand-binding pocket in 5-HT2AR significantly differs around extracellular loops 1 and 2 from that in D2R. These findings are beneficial for the rational design of safer antipsychotics and 5-HT2AR-selective drugs.

In addition to the serotonin 5-HT2A receptor (5-HT2AR), the dopamine D2 receptor (D2R) is a key therapeutic target of antipsychotics for the treatment of schizophrenia. The inactive state structures of D2R have been described in complex with the inverse agonists risperidone (D2Rris) and haloperidol (D2Rhal). Here we describe the structure of human D2R in complex with spiperone (D2Rspi). In D2Rspi, the conformation of the extracellular loop (ECL) 2, which composes the ligand-binding pocket, was substantially different from those in D2Rris and D2Rhal, demonstrating that ECL2 in D2R is highly dynamic. Moreover, D2Rspi exhibited an extended binding pocket to accommodate spiperone’s phenyl ring, which probably contributes to the selectivity of spiperone to D2R and 5-HT2AR. Together with D2Rris and D2Rhal, the structural information of D2Rspi should be of value for designing novel antipsychotics with improved safety and efficacy., 統合失調症に関わるドパミン受容体の構造解明 --副作用を抑えた薬の迅速な探索・設計が可能に--. 京都大学プレスリリース. 2020-12-24.

Metabolic activities are altered in cancer cells compared with those in normal cells, and the cancer-specific pathway becomes a potential therapeutic target. Higher cellular glucose consumption, which leads to lower glucose levels, is a hallmark of cancer cells. In an objective screening for chemicals that induce cell death under low-glucose conditions, we discovered a compound, denoted as ALESIA (Anticancer Ligand Enhancing Starvation-induced Apoptosis). By our shedding assay of transforming growth factor α in HEK293A cells, ALESIA was determined to act as a sphingosine-1-phosphate receptor 3-G

The carbon fiber reinforced plastics (CFRP) are still limited the used in the automotive industry mainly by the weak interfacial adhesion between the fiber and polymer matrix. Herein, to improve interfacial interactions between the carbon fiber (CF) and polypropylene (PP) matrix, poly(dimethylaminoethyl methacrylate)-b-poly(methyl methacrylate) (PDMAEMA-b-PMMA, PDM) compatibilizers are applied to functionalize the CF surface through a covalent bonding with epoxide groups on the chemically modified CF surface with tertiary amines in the PDMAEMA block, which induced intermolecular entanglement with PP chains with the PMD compatibilizers. The acquired compatibilizer-functionalized CF (CECF) was applied to fabricate PP composites by a melt-mixing method. The highly improved interfacial adhesion between the CECF and PP was confirmed by evaluating thermal, morphological, rheological, and mechanical properties. Based on the significantly enhanced interfacial adhesion, notably, the tensile strength and modulus of the CECF/PP composite exhibited a massive increase by ca. 312% and 664%, respectively, relative to those of the PP resin. The Ashby plot facilitated understanding that the acquired mechanical properties of the CECF/PP composite showed a relatively ideal position compared to reported PP composites and centered on the commercially available region in automotive components.

Metabolic activities are altered in cancer cells compared with those in normal cells, and the cancer-specific pathway becomes a potential therapeutic target. Higher cellular glucose consumption, which leads to lower glucose levels, is a hallmark of cancer cells. In an objective screening for chemicals that induce cell death under low-glucose conditions, we discovered a compound, denoted as ALESIA (Anticancer Ligand Enhancing Starvation-induced Apoptosis). By our shedding assay of transforming growth factor α in HEK293A cells, ALESIA was determined to act as a sphingosine-1-phosphate receptor 3-G12-biased agonist that promotes nitric oxide production and oxidative stress. The oxidative stress triggered by ALESIA resulted in the exhaustion of glucose, cellular NADPH deficiency, and then cancer cell death. Intraperitoneal administration of ALESIA improved the survival of mice with peritoneally disseminated rhabdomyosarcoma, indicating its potential as a new type of anticancer drug for glucose starvation therapy.

Summary Angiotensin II (AngII) is a peptide hormone that plays a key role in regulating blood pressure, and its interactions with the G protein-coupled receptors, AngII type-1 receptor (AT1R) and AngII type-2 receptor (AT2R), are central to its mechanism of action. We solved the crystal structure of human AT2R bound to AngII and its specific antibody at 3.2-A resolution. AngII (full agonist) and [Sar1, Ile8]-AngII (partial agonist) interact with AT2R in a similar fashion, except at the bottom of the AT2R ligand-binding pocket. In particular, the residues including Met1283.36, which constitute the deep end of the cavity, play important roles in angiotensin receptor (ATR) activation upon AngII binding. These differences that occur upon endogenous ligand binding may contribute to a structural change in AT2R, leading to normalization of the non-canonical coordination of helix 8. Our results will inform the design of more effective ligands for ATRs.

Many drugs target the serotonin 2A receptor (5-HT

l‐Amino acid oxidase/monooxygenase from Pseudomonas sp. AIU 813 (l‐AAO/MOG) catalyzes both the oxidative deamination and oxidative decarboxylation of the α‐group of l‐Lys to produce a keto acid and amide, respectively. l‐AAO/MOG exhibits limited specificity for l‐amino acid substrates with a basic side chain. We previously determined its ligand‐free crystal structure and identified a key residue for maintaining the dual activities. Here, we determined the structures of l‐AAO/MOG complexed with l‐Lys, l‐ornithine, and l‐Arg and revealed its substrate recognition. Asp238 is located at the ceiling of a long hydrophobic pocket and forms a strong interaction with the terminal, positively charged group of the substrates. A mutational analysis on the D238A mutant indicated that the interaction is critical for substrate binding but not for catalytic control between the oxidase/monooxygenase activities. The catalytic activities of the D238E mutant unexpectedly increased, while the D238F mutant exhibited altered substrate specificity to long hydrophobic substrates. In the ligand‐free structure, there are two channels connecting the active site and solvent, and a short region located at the dimer interface is disordered. In the l‐Lys complex structure, a loop region is displaced to plug the channels. Moreover, the disordered region in the ligand‐free structure forms a short helix in the substrate complex structures and creates the second binding site for the substrate. It is assumed that the amino acid substrate enters the active site of l‐AAO/MOG through this route. Database The atomic coordinates and structure factors (codes 5YB6, 5YB7, and 5YB8) have been deposited in the Protein Data Bank (http://wwpdb.org/). EC numbers 1.4.3.2 (l‐amino acid oxidase), 1.13.12.2 (lysine 2‐monooxygenase).

Snapshots of bacteriorhodopsin Bacteriorhodopsin is a membrane protein that harvests the energy content from light to transport protons out of the cell against a transmembrane potential. Nango et al. used timeresolved serial femtosecond crystallography at an x-ray free electron laser to provide 13 structural snapshots of the conformational changes that occur in the nanoseconds to milliseconds after photoactivation. These changes begin at the active site, propagate toward the extracellular side of the protein, and mediate internal protonation exchanges that achieve proton transport. Science , this issue p. 1552