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51.
Christina Bergonzo Kunal Dharmadhikari Emily Samuels Makenzie Christensen Jennifer Tullman 《Proteins》2020,88(9):1189-1196
ClpS2 is a small protein under development as a probe for selectively recognizing N-terminal amino acids of N-degron peptide fragments. To understand the structural basis of ClpS2 specificity for an N-terminal amino acid, all atom molecular dynamics (MD) simulations were conducted using the sequence of a bench-stable mutant of ClpS2, called PROSS. We predicted that a single amino acid leucine to asparagine substitution would switch the specificity of PROSS ClpS2 to an N-terminal tyrosine over the preferred phenylalanine. Experimental validation of the mutant using a fluorescent yeast-display assay showed an increase in tyrosine binding over phenylalanine, in support of the proposed hypothesis. 相似文献
52.
Walter Keung Amogh Boloor Jason Brown Andre Kiryanov Anthony Gangloff J. David Lawson Robert Skene Isaac Hoffman Josephine Atienza Jason Kahana Ron De Jong Pamela Farrell Deepika Balakrishna Petro Halkowycz 《Bioorganic & medicinal chemistry letters》2017,27(4):1099-1104
Axl has been a target of interest in the oncology field for several years based on its role in various oncogenic processes. To date, no wild-type Axl crystal structure has been reported. Herein, we describe the structure-based optimization of a novel chemotype of Axl inhibitors, 1H-imidazole-2-carboxamide, using a mutated kinase homolog, Mer(I650M), as a crystallographic surrogate. Iterative optimization of the initial lead compound (1) led to compound (21), a selective and potent inhibitor of wild-type Axl. Compound (21) will serve as a useful compound for further in vivo studies. 相似文献
53.
Barbara C. Klump Jessica E. M. van der Wal James J. H. St Clair Christian Rutz 《Proceedings. Biological sciences / The Royal Society》2015,282(1808)
Several animal species use tools for foraging, such as sticks to extract embedded arthropods and honey, or stones to crack open nuts and eggs. While providing access to nutritious foods, these behaviours may incur significant costs, such as the time and energy spent searching for, manufacturing and transporting tools. These costs can be reduced by re-using tools, keeping them safe when not needed. We experimentally investigated what New Caledonian crows do with their tools between successive prey extractions, and whether they express tool ‘safekeeping’ behaviours more often when the costs (foraging at height), or likelihood (handling of demanding prey), of tool loss are high. Birds generally took care of their tools (84% of 176 prey extractions, nine subjects), either trapping them underfoot (74%) or storing them in holes (26%)—behaviours we also observed in the wild (19 cases, four subjects). Moreover, tool-handling behaviour was context-dependent, with subjects: keeping their tools safe significantly more often when foraging at height; and storing tools significantly more often in holes when extracting more demanding prey (under these conditions, foot-trapping proved challenging). In arboreal environments, safekeeping can prevent costly tool losses, removing a potentially important constraint on the evolution of habitual and complex tool behaviour. 相似文献
54.
Jesús Banda‐Vázquez Sooruban Shanmugaratnam Rogelio Rodríguez‐Sotres Alfredo Torres‐Larios Birte Höcker Alejandro Sosa‐Peinado 《Protein science : a publication of the Protein Society》2018,27(5):957-968
Computational protein design is still a challenge for advancing structure‐function relationships. While recent advances in this field are promising, more information for genuine predictions is needed. Here, we discuss different approaches applied to install novel glutamine (Gln) binding into the Lysine/Arginine/Ornithine binding protein (LAOBP) from Salmonella typhimurium. We studied the ligand binding behavior of two mutants: a binding pocket grafting design based on a structural superposition of LAOBP to the Gln binding protein QBP from Escherichia coli and a design based on statistical coupled positions. The latter showed the ability to bind Gln even though the protein was not very stable. Comparison of both approaches highlighted a nonconservative shared point mutation between LAOBP_graft and LAOBP_sca. This context dependent L117K mutation in LAOBP turned out to be sufficient for introducing Gln binding, as confirmed by different experimental techniques. Moreover, the crystal structure of LAOBP_L117K in complex with its ligand is reported. 相似文献
55.
Yusuf Oloruntoyin AYIPO Sani Najib YAHAYA Halimah Funmilayo BABAMALE Iqrar AHMAD Harun PATEL Mohd Nizam MORDI 《Turkish Journal of Biology》2021,45(4):503
The nsp3 macrodomain is implicated in the viral replication, pathogenesis and host immune responses through the removal of ADP-ribosylation sites during infections of coronaviruses including the SARS-CoV-2. It has ever been modulated by macromolecules including the ADP-ribose until Ni and co-workers recently reported its inhibition and plasticity enhancement unprecedentedly by remdesivir metabolite, GS-441524, creating an opportunity for investigating other biodiverse small molecules such as β-Carboline (βC) alkaloids. In this study, 1497 βC analogues from the HiT2LEAD chemical database were screened, using computational approaches of Glide XP docking, molecular dynamics simulation and pk-CSM ADMET predictions. Selectively, βC ligands, 129, 584, 1303 and 1323 demonstrated higher binding affinities to the receptor, indicated by XP docking scores of –10.72, –10.01, –9.63 and –9.48 kcal/mol respectively than remdesivir and GS-441524 with –4.68 and –9.41 kcal/mol respectively. Consistently, their binding free energies were –36.07, –23.77, –24.07 and –17.76 kcal/mol respectively, while remdesivir and GS-441524 showed –21.22 and –24.20 kcal/mol respectively. Interestingly, the selected βC ligands displayed better stability and flexibility for enhancing the plasticity of the receptor than GS-441524, especially 129 and 1303. Their predicted ADMET parameters favour druggability and low expressions for toxicity. Thus, they are recommended as promising adjuvant/standalone anti-SARS-CoV-2 candidates for further study.Key words: SARS-CoV-2, nsp3 macrodomain, ADP-ribose, β-carboline, bioinformatics, drug design 相似文献
56.
57.
Yugang Zhang Huaiqing Cao Zhirong Liu 《Protein science : a publication of the Protein Society》2015,24(5):688-705
To assess the potential of intrinsically disordered proteins (IDPs) as drug design targets, we have analyzed the ligand-binding cavities of two datasets of IDPs (containing 37 and 16 entries, respectively) and compared their properties with those of conventional ordered (folded) proteins. IDPs were predicted to possess more binding cavity than ordered proteins at similar length, supporting the proposed advantage of IDPs economizing genome and protein resources. The cavity number has a wide distribution within each conformation ensemble for IDPs. The geometries of the cavities of IDPs differ from the cavities of ordered proteins, for example, the cavities of IDPs have larger surface areas and volumes, and are more likely to be composed of a single segment. The druggability of the cavities was examined, and the average druggable probability is estimated to be 9% for IDPs, which is almost twice that for ordered proteins (5%). Some IDPs with druggable cavities that are associated with diseases are listed. The optimism versus obstacles for drug design for IDPs is also briefly discussed. 相似文献
58.
Rocio Duque‐Jamaica Azucena Arévalo‐Galvis Raúl A. Poutou‐Piñales Alba A. Trespalacios 《Helicobacter》2010,15(4):303-312
Background: Colonization of the gastric mucosa by Helicobacter pylori is one of the most important causes of acute and chronic gastric pathologies in humans. Achieving the growth of H. pylori in liquid media is of great importance in the development of clinical studies. In this study, we developed a sequential optimization strategy based on statistical models to improve the conditions of liquid culture of H. pylori. Materials and Methods: Four statistical models were sequentially used. First, a Box‐Behnken design was used to select the best process conditions (shaking speed, inoculum concentration, and final volume of culture). Secondly, a general factorial design was used to evaluate the influence of adding gel blocks or gel beads (shape and composition). Then a D‐optimal reduce design was carried out to allow the selection of the most influential factors in increasing the cell concentration (culture media components). Finally, another Box‐Behnken design was used to optimize the concentration of the culture media components previously selected. Results: After 12 hours of liquid culture a concentration of 25 × 108 cells per mL (9.4 log10 cells per mL) of H. pylori was obtained, compared with a predicted 32 × 108 (9.5 log10 cells per mL), which means between 1 and 5 log10 units higher than some previous reports. Conclusions: The sequential statistical approach increased the planktonic H. pylori cell culture. The final culture media and conditions were: Brain Heart Infusion, blood agarose (1.5% w/v), lamb’s blood (3.18% v/v), DENT (0.11% v/v), and Vitox (0.52% v/v) at 60 rpm and 37 °C with filtered CO2 (5% v/v) bubbled directly into the culture media in a final volume of 76.22 mL. 相似文献
59.
R. A. Ndzana A. Magro L. Bedoussac E. Justes E.‐P. Journet J.‐L. Hemptinne 《Journal of Applied Entomology》2014,138(8):577-585
Acyrthosiphon pisum Harris (Aphididae: Hemiptera), the pea aphid, is an important pest in organic farming systems. In this work, the objective was to gather empirical field data on the associational resistance of durum wheat–winter pea intercrops towards the pea aphid, compared with pure stands of winter pea. Our results showed that intercropping winter pea with durum wheat significantly decreased A. pisum abundance in all the situations. Moreover, it was systematically observed that pea grew bigger in pure than in intercropped stands but after considering pea dry mass as a covariate, it appeared that the durum wheat–winter pea intercrop was still significantly less attacked by pea aphids than the sole crop. Intercrop sowing designs had an incidence on infestation levels: substitutive diversification systems of different types are more effective in decreasing the level of aphid infestation than does the additive system. In addition, substitutive row intercrop is significantly less infested than substitutive mixture. These results suggest that a mechanism related to the resource concentration hypothesis may explain the associational resistance of the IC of durum wheat–winter pea towards A. pisum. 相似文献
60.