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ACS Chemical Biology

Milton Cordeiro, Ana Rita Otrelo-Cardoso, Dmitri I Svergun, Petr V Konarev, João Carlos Lima, Teresa Santos-Silva, Pedro Viana Baptista
Selective base pairing is the foundation of DNA recognition. Here, we elucidate the molecular and structural details of a FRET-based two-component molecular beacon relying on Steady-state Fluorescence Spectroscopy, Small-angle X-ray Scattering (SAXS), Microscale Thermophoresis (MST) and Differential Electrophoretic Mobility. This molecular beacon was designed to detect the most common fusion sequences causing chronic myeloid leukemia, e14a2 and e13a2. The emission spectra indicate that the self-assembly of the different components of the biosensor occurs sequentially, triggered by the fully complementary target...
March 21, 2018: ACS Chemical Biology
Peter D Koch, Howard R Miller, Gary Yu, John A Tallarico, Peter K Sorger, Yuan Wang, Yan Feng, Jason R Thomas, Nathan T Ross, Timothy Mitchison
We screened a library of bioactive small molecules for activators and inhibitors of innate immune signaling through IRF3 and NFkB pathways with the goals of advancing pathway understanding and discovering probes for immunology research. We used high content screening to measure the translocation from the cytoplasm to nucleus of IRF3 and NFkB in primary human macrophages; these transcription factors play a critical role in the activation of STING and other pro-inflammatory pathways. Our pathway activator screen yielded a diverse set of hits that promoted nuclear translocation of IRF3 and/or NFkB, but the majority of these compounds did not cause activation of downstream pathways...
March 19, 2018: ACS Chemical Biology
K M Noh, C D Allis, H Li
No abstract text is available yet for this article.
March 16, 2018: ACS Chemical Biology
Yunan Zheng, Martin J Gilgenast, Sacha Hauc, Abhishek Chatterjee
Reversible post-translational modification (PTM) is a powerful and ubiquitous mechanism to regulate protein function. The mechanistic basis of the associated functional regulation by PTMs often involves the recruitment of interaction partners that selectively binds the modified protein. Identifying such functionally important protein-protein interactions that are uniquely triggered by PTMs remains difficult due to several technical challenges. To address this, here we develop technology to site-specifically incorporate two distinct noncanonical amino acids into recombinant proteins: one modeling a PTM of interest and the second harboring a photoaffinity probe...
March 15, 2018: ACS Chemical Biology
Geng Li, Chenhui He, Peixuan Bu, Huimin Bi, Sichen Pan, Ronghua Sun, Xin Sheng Zhao
Skp and SurA are both periplasmic chaperones involved in the biogenesis of E. coli β-barrel outer membrane proteins (OMPs). It is commonly assumed that SurA plays a major role, whereas Skp is a minor factor. However, there is no molecular evidence for whether their roles are redundant or not. Here, by using different dilution methods, we obtained monodisperse and aggregated forms of OmpC and studied their interactions with Skp and SurA by single-molecule fluorescence resonance energy transfer (smFRET) and fluorescence correlation spectroscopy (FCS)...
March 15, 2018: ACS Chemical Biology
James W Checco, Guo Zhang, Wangding Yuan, Ke Yu, Siyuan Yin, Rachel H Roberts-Galbraith, Peter M Yau, Elena V Romanova, Jian Jing, Jonathan V Sweedler
Neuropeptides in several animals undergo an unusual post-translational modification: the isomerization of an amino acid residue from the L-stereoisomer to the D-stereoisomer. The resulting D-amino acid-containing peptide (DAACP) often displays higher biological activity than its all-L-residue analogue, with the D-residue being critical for function in many cases. However, little is known about the full physiological roles played by DAACPs and few studies have examined the interaction of DAACPs with their cognate receptors...
March 15, 2018: ACS Chemical Biology
John B McArthur, Hai Yu, Nova Tasnima, Christie M Lee, Andrew J Fisher, Xi Chen
The lack of α2-6-linkage specific sialidases limits the structural and functional studies of sialic acid-containing molecules. Photobacterium damselae α2-6-sialyltransferase (Pd2,6ST) was shown previously to have α2-6-specific, but weak, sialidase activity. Here we develop a high-throughput blue-white colony screening method to identify Pd2,6ST mutants with improved α2-6-sialidase activity from mutant libraries generated by sequential saturation mutagenesis. A triple mutant (Pd2,6ST S232L/T356S/W361F) has been identified with 101-fold improved activity, high α2-6-sialyl linkage selectivity, good activity in cleaving two common sialic acid forms N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc)...
March 15, 2018: ACS Chemical Biology
Kelvin J Yong, Tasneem M Vaid, Patrick J Shilling, Feng-Jie Wu, Lisa M Williams, Mattia Deluigi, Andreas Plückthun, Ross Ad Bathgate, Paul R Gooley, Daniel J Scott
α1A- and α1B-adrenoceptors (α1A-AR and α1B-AR) are closely related G protein-coupled receptors (GPCRs) that modulate the cardiovascular and nervous systems in response to binding epinephrine and norepinephrine. The GPCR gene super-family is made up of numerous sub-families that, like α1A-AR and α1B-AR, are activated by the same endogenous agonists but may modulate different physiological processes. A major challenge in GPCR research and drug discovery is determining how compounds interact with receptors at the molecular level, especially to assist in the optimization of drug leads...
March 14, 2018: ACS Chemical Biology
Xinxing Zhang, Yuting Wang, David H Perez, Rachel A Jones Lipinski, Rebecca A Butcher
Caenorhabditis elegans produces a complex mixture of ascaroside pheromones to control its development and behavior. Acyl-CoA oxidases, which participate in β-oxidation cycles that shorten the side chains of the ascarosides, regulate the mixture of pheromones produced. Here, we use CRISPR-Cas9 to make specific nonsense and missense mutations in acox genes and determine the effect of these mutations on ascaroside production in vivo. Ascaroside production in acox-1.1 deletion and nonsense strains, as well as a strain with a missense mutation in a catalytic residue, confirms the central importance of ACOX-1...
March 14, 2018: ACS Chemical Biology
Michel Weïwer, Qihong Xu, Jennifer P Gale, Michael Lewis, Arthur J Campbell, Frederick A Schroeder, Genevieve C Van de Bittner, Michelle Walk, Aldo Amaya, Ping Su, Luka D Ordevic, Joshua R Sacher, Adam Skepner, David Fei, Kelly Dennehy, Shannon Nguyen, Patrick W Faloon, Jose Perez, Jeffrey R Cottrell, Fang Liu, Michelle Palmer, Jen Q Pan, Jacob M Hooker, Yan-Ling Zhang, Edward Scolnick, Florence F Wagner, Edward B Holson
Schizophrenia is a severe neuropsychiatric disease that lacks completely effective and safe therapies. As a polygenic disorder, genetic studies have only started to shed light on its complex etiology. To date, the positive symptoms of schizophrenia are well-managed by antipsychotic drugs, which primarily target the dopamine D2 receptor (D2R). However, these antipsychotics are often accompanied by severe side effects, including motoric symptoms. At D2R, antipsychotic drugs antagonize both G-protein dependent (Gαi/o ) signaling and G-protein independent (β-arrestin) signaling...
March 14, 2018: ACS Chemical Biology
Elizabeth I Parkinson, James H Tryon, Anthony W Goering, Kou-San Ju, Ryan A McClure, Jeremy D Kemball, Sara Zhukovsky, David P Labeda, Regan J Thomson, Neil L Kelleher, William W Metcalf
Natural products (NPs) are a rich source of medicines, but traditional discovery methods are often unsuccessful due to high rates of rediscovery. Genetic approaches for NP discovery are promising, but progress has been slow due to the difficulty of identifying unique biosynthetic gene clusters (BGCs) and poor gene expression. We previously developed the metabologenomics method, which combines genomic and metabolomic data to discover new NPs and their BGCs. Here, we utilize metabologenomics in combination with molecular networking to discover a novel class of NPs, the tyrobetaines: nonribosomal peptides with an unusual trimethylammonium tyrosine residue...
March 13, 2018: ACS Chemical Biology
Gayan Mirihana Arachchilage, Prakash Kharel, Joshua Reid, Soumitra Basu
Since the elevated levels of microRNAs (miRNAs) often cause various diseases, selective inhibition of miRNA maturation is an important therapeutic strategy. Commonly used anti-miRNA strategies are limited to targeting of mature miRNAs, as the upstream targeting of miRNA maturation with an oligonucleotide is challenging due to the presence of stable pre-miRNA stem-loop structure. Previously, we reported that about 16% of known human pre-miRNAs have the potential to adopt G-quadruplex (GQ) structures alternative to canonical stem-loops...
March 12, 2018: ACS Chemical Biology
Anastasia Amato, Xavier Lucas, Alessio Bortoluzzi, David Wright, Alessio Ciulli
Plant homeodomain (PHD) zinc fingers are histone reader domains that often associate with human diseases. Despite this, they constitute a poorly targeted class of readers, suggesting low ligandability. Here, we describe a successful fragment-based campaign targeting PHD fingers from the proteins BAZ2A and BAZ2B as model systems. We validated a pool of in silico fragments both biophysically and structurally and solved the first crystal structures of PHD zinc fingers in complex with fragments bound to an anchoring pocket at the histone binding site...
March 12, 2018: ACS Chemical Biology
Hailey J Knox, Tae Wook Kim, Zhouyang Zhu, Jefferson Chan
Hypoxia results when the oxygen supply to rapidly growing tumors becomes inadequate to support various physiological processes. This plays a role in tumor metastasis and treatment resistance. Therefore, identifying tumor hypoxia can guide treatment planning and predict patient responses. However, hypoxic volumes are heterogeneously dispersed throughout a tumor, making it a challenge to pinpoint them with any degree of accuracy. Herein, we report the development of ratiometric hypoxia probe 1 (rHyP-1), which is a hypoxia-responsive small-molecule probe designed for reliable hypoxia detection using photoacoustic imaging...
March 9, 2018: ACS Chemical Biology
Santanu Mondal, Sangram S Parelkar, Mitesh Nagar, Paul R Thompson
Protein Arginine deiminases (PADs) play an important role in the pathogenesis of various diseases, including rheumatoid arthritis, multiple sclerosis, lupus, ulcerative colitis and breast cancer. Therefore, the development of PAD-inhibitors has drawn significant research interest in recent years. Herein, we describe the development of the first photoswitchable PAD-inhibitors. These compounds possess an azobenzene photoswitch to optically control PAD activity. Screening of a series of inhibitors structurally similar to BB-Cl-Amidine afforded compounds 1 and 2 as the most promising candidates for the light-controlled inhibition of PAD2; the cis-isomer of 1 is 10-fold more potent than its trans-isomer, whereas the trans-isomer of 2 is 45-fold more potent than the corresponding cis-isomer...
March 8, 2018: ACS Chemical Biology
Michael M Gaschler, Fanghao Hu, Huizhong Feng, Andreas Linkermann, Wei Min, Brent R Stockwell
Ferroptosis is a form of non-apoptotic cell death characterized by the unchecked accumulation of lipid peroxides. Ferrostatin-1 and its analogs (ferrostatins) specifically prevent ferroptosis in multiple contexts, but many aspects of their molecular mechanism of action remain poorly described. Here, we employed stimulated Raman scattering (SRS) microscopy coupled with small vibrational tags to image the distribution of ferrostatins in cells, and found that they accumulate in lysosomes, mitochondria, and endoplasmic reticulum...
March 7, 2018: ACS Chemical Biology
Jiasong Jiang, Daisy Guiza Beltran, Andrew Schacht, Stephen Wright, Limei Zhang, Liangcheng Du
Myxin is a well-known antibiotic that had been used for decades. It belongs to the phenazine natural products that exhibit various biological activities, which are often dictated by the decorating groups on the heteroaromatic three-ring system. The three rings of myxin carry a number of decorations, including an unusual aromatic N5, N10-dioxide. We previously showed that phenazine 1,6-dicarboxylic acid (PDC) is the direct precursor of myxin and two redox enzymes (LaPhzS and LaPhzNO1) catalyze the decarboxylative hydroxylation and aromatic N-oxidations of PDC to produce iodinin (1...
March 6, 2018: ACS Chemical Biology
Simon Wisnovsky, Tanja Sack, David J Pagliarini, Rebecca R Laposa, Shana O Kelley
Replication and maintenance of mitochondrial DNA (mtDNA) is essential for cellular function, yet few DNA polymerases are known to function in mitochondria. Here, we conclusively demonstrate that DNA polymerase θ (Polθ) localizes to mitochondria and explore whether this protein is overexpressed in patient-derived cells and tumors. Polθ appears to play an important role in facilitating mtDNA replication under conditions of oxidative stress, and this error-prone polymerase was found to introduce mutations into mtDNA...
March 6, 2018: ACS Chemical Biology
Yogan Khatri, Ilona K Jóźwik, Michael Ringle, Irina Alexandra Ionescu, Martin Litzenburger, Michael Christopher Hutter, Andy-Mark W H Thunnissen, Rita Bernhardt
The production of regio- and stereoselectively hydroxylated steroids is of high pharmaceutical interest and can be achieved by cytochrome P450-based biocatalysts. CYP260A1 from Sorangium cellulosum strain So ce56 catalyzes hydroxylation of C19 or C21 steroids at the very unique 1-position. However, the conversion of progesterone (PROG) by CYP260A1 is very unselective. In order to improve its selectivity we applied a semi-rational protein engineering approach, resulting in two different, highly regio- and stereoselective mutants by replacing a single serine residue (S276) of the substrate recognition site 5 with an asparagine or isoleucine...
March 6, 2018: ACS Chemical Biology
Eric McGivney, Kayleigh Elizabeth Jones, Bandrea Weber, Ann Margaret Valentine, Jeanne M Vanbriesen, Kelvin B Gregory
Quorum sensing (QS) regulates important bacterial behaviors such as virulent protein production and biofilm formation. QS requires that molecular signals are exchanged between cells, extracellularly, where environmental conditions influence signal stability. In this work, we present a novel complexation between metal cations (Ag+ and Cu2+ ) and a QS autoinducer signal, N-hexanoyl-homoserine lactone (HHL). The molecular interactions were investigated using mass spectrometry, attenuated total reflectance-Fourier transform infrared spectroscopy, and computational simulations...
March 6, 2018: ACS Chemical Biology
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