- Journal article
Authors : Verma, Kanika; Saxena, Kanika; Donaka, Rajashekar (2020) - Changes in metabolism can alter the cellular milieu; can this also change intracellular proteostasis? Since proteostasis can modulate mutational buffering, if change in metabolism has the ability to change proteostasis, arguably, it should also alter mutational buffering. Building on this, we find that altered cellular metabolic states in E. coli buffer distinct mutations. Buffered-mutants had folding problems in vivo and were differently chaperoned in different m...
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- Journal article
Authors : Asquith, Christopher R. M; Tizzard, Graham J; Bennett, James M (2020) - Water networks within kinase inhibitor design and more widely within drug discovery are generally poorly understood. The successful targeting of these networks prospectively has great promise for all facets of inhibitor design, including potency and selectivity on target. Here we describe the design and testing of a targeted library of 4-anilinoquinolines for use as inhibitors of cyclin G associated kinase (GAK). The GAK cellular target engagement assays,...
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- Journal article
Authors : Kirykowicz, Angela M; Woodward, Jeremy D (2020) - Large protein complexes play key roles in mediating biological processes in the cell. Little structural information is known on the protein complex mediators governing persistence in the host for Mycobacterium tuberculosis (Mtb). We applied the ‘shotgun EM’ method for the structural characterisation of protein complexes produced after exposure to stationary phase stress for the model Mycobacterium, M smegmatis (Msm). We identified glutamine synthetase I, essential ...
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- Journal article
Authors : Bohr, Søren S.-R; Thorlaksen, Camilla; Kühnel, Ronja Marie (2020) - Lipases are important hydrolytic enzymes used in a spectrum of technological applications, such as the pharmaceutical and detergent industry. Due to their versatile nature and ability to accept a broad range of substrates they have been extensively used for biotechnological and industrial applications. Current assays to measure lipase activity primarily rely on low sensitivity measurement of pH variations or visible changes on material properties, like hydration,&...
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- Journal article
Authors : Speltz, Elizabeth B; Zalatan, Jesse G (2020) - Scaffold proteins are thought to accelerate protein phosphorylation reactions by tethering kinases and substrates together, but there is little quantitative data on their functional effects. To assess the contribution of tethering to kinase reactivity, we compared intramolecular and intermolecular kinase reactions in a minimal model system. We find that tethering can enhance reaction rates in a flexible tethered kinase system, and the magnitude of the effect ...
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- Journal article
Authors : Cornelison, Jeffery L; Cato, Michael L; Johnson, Alyssa M (2020) - LRH-1 is a nuclear receptor that regulates lipid metabolism and homeostasis, making it an attractive target for the treatment of diabetes and non-alcoholic fatty liver disease. Building on recent structural information about ligand binding from our labs, we have designed a series of new LRH-1 agonists that further engage LRH-1 through added polar interactions. While the current synthetic approach to this scaffold has, in large part, allowed for deco...
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- Journal article
Authors : Khandagale, Prashant; Thakur, Shweta; Acharya, Narottam (2020) - DNA polymerase delta (Polδ) is a highly processive essential replicative DNA polymerase. In humans, Polδ holoenzyme consists of p125, p50, p68, and p12 subunits and recently, we have shown that p12 exists as a dimer. Extensive biochemical studies suggest that all the subunits of Polδ interact with the processivity factor proliferating cell nuclear antigen (PCNA) to carry out a pivotal role in genomic DNA replication. While PCNA interaction protein&#...
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- Journal article
Authors : McSweeney, Donal M; McSweeney, Sean M; Liu, Qun (2020) - High-resolution single-particle cryo-EM data analysis relies on accurate particle picking. To facilitate the particle picking process, we have developed a self-supervised workflow. Our workflow includes an iterative strategy to use the 2D class average to improve training particles and a progressively improved convolutional neural network (CNN) for particle picking. To automate the selection of particles, we define a threshold (%/Res) using the ratio of percentage...
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- Journal article
Authors : Alghamdi, Ali H; Munday, Jane C; Campagnaro, Gustavo D (2020) - Mutations in the Trypanosoma brucei aquaporin AQP2 are associated with resistance to pentamidine and melarsoprol. We show that TbAQP2 but not TbAQP3 was positively selected for increased pore size from a common ancestor aquaporin. We demonstrate that TbAQP2’s unique architecture permits pentamidine permeation through its central pore and show how specific mutations in highly conserved motifs affect drug permeation. Introduction of key TbAQP2 amino acids into ...
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- Journal article
Authors : Andersen, Susan; Møller, Marie S; Poulsen, Jens-Christian N (2020) - The maltooligosaccharide (MOS) utilization locus in The degradation of starch in the small intestine generates short linear and branched α-glucans. The latter are poorly digestible by humans, rendering them available to the gut microbiota e.g. lactobacilli adapted to the human small intestine and considered as beneficial to health. This study unveils a previously unknown scheme of maltooligosaccharide (MOS) catabolism, via the concerted action of activity together...
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