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Cell Chemical Biology

Mayeul Collot, Pichandi Ashokkumar, Halina Anton, Emmanuel Boutant, Orestis Faklaris, Thierry Galli, Yves Mély, Lydia Danglot, Andrey S Klymchenko
The proper staining of the plasma membrane (PM) is critical in bioimaging as it delimits the cell. Herein, we developed MemBright, a family of six cyanine-based fluorescent turn-on PM probes that emit from orange to near infrared when reaching the PM, and enable homogeneous and selective PM staining with excellent contrast in mono- and two-photon microscopy. These probes are compatible with long-term live-cell imaging and immunostaining. Moreover, MemBright label neurons in a brighter manner than surrounding cells, allowing identification of neurons in acute brain tissue sections and neuromuscular junctions without any use of transfection or transgenic animals...
February 6, 2019: Cell Chemical Biology
Roman S Erdmann, Stephanie Wood Baguley, Jennifer H Richens, Rebecca F Wissner, Zhiqun Xi, Edward S Allgeyer, Sheng Zhong, Alexander D Thompson, Nicholas Lowe, Richard Butler, Joerg Bewersdorf, James E Rothman, Daniel St Johnston, Alanna Schepartz, Derek Toomre
Super-resolution microscopy requires that subcellular structures are labeled with bright and photostable fluorophores, especially for live-cell imaging. Organic fluorophores may help here as they can yield more photons-by orders of magnitude-than fluorescent proteins. To achieve molecular specificity with organic fluorophores in live cells, self-labeling proteins are often used, with HaloTags and SNAP-tags being the most common. However, how these two different tagging systems compare with each other is unclear, especially for stimulated emission depletion (STED) microscopy, which is limited to a small repertoire of fluorophores in living cells...
February 4, 2019: Cell Chemical Biology
Qian Xie, Aishan Zhao, Philip D Jeffrey, Minyoung Kevin Kim, Bonnie L Bassler, Howard A Stone, Richard P Novick, Tom W Muir
Virulence induction in the Staphylococcus aureus is under the control of a quorum sensing (QS) circuit encoded by the accessory gene regulator (agr) locus. Allelic variation within agr produces four QS specificity groups, each producing a unique secreted autoinducer peptide (AIP) and receptor histidine kinase (RHK), AgrC. Cognate AIP-AgrC interactions activate virulence through a two-component signaling cascade, whereas non-cognate pairs are generally inhibitory. Here we pinpoint a key hydrogen-bonding interaction within AgrC that acts as a switch to convert helical motions propagating from the receptor sensor domain into changes in inter-domain association within the kinase module...
January 31, 2019: Cell Chemical Biology
Dharmaraja Allimuthu, Zita Hubler, Fadi J Najm, Hong Tang, Ilya Bederman, William Seibel, Paul J Tesar, Drew J Adams
Small molecules that promote oligodendrocyte formation have been identified in "drug repurposing" screens to nominate candidate therapeutics for diseases in which myelin is lost, including multiple sclerosis. We recently reported that many such molecules enhance oligodendrocyte formation not by their canonical targets but by inhibiting a narrow range of enzymes in cholesterol biosynthesis. Here we identify enhancers of oligodendrocyte formation obtained by screening a structurally diverse library of 10,000 small molecules...
January 31, 2019: Cell Chemical Biology
Mingxu You, Jacob L Litke, Rigumula Wu, Samie R Jaffrey
Genetically encoded biosensors are useful tools for detecting the presence and levels of diverse biomolecules in living cells. However, low-abundance targets are difficult to detect because they are often unable to bind and activate enough biosensors to detect using standard microscopic imaging approaches. Here we describe a type of RNA-based biosensor, an RNA integrator, which enables detection of low-abundance targets in vitro and in living cells. The RNA integrator is an RNA sequence comprising a ribozyme and an unfolded form of the fluorogenic aptamer Broccoli...
January 25, 2019: Cell Chemical Biology
Chao Gao, Melinda S Hanes, Lauren A Byrd-Leotis, Mohui Wei, Nan Jia, Robert J Kardish, Tanya R McKitrick, David A Steinhauer, Richard D Cummings
The glycan ligands recognized by Siglecs, influenza viruses, and galectins, as well as many plant lectins, are not well defined. To explore their binding to asparagine (Asn)-linked N-glycans, we synthesized a library of isomeric multiantennary N-glycans that vary in terminal non-reducing sialic acid, galactose, and N-acetylglucosamine residues, as well as core fucose. We identified specific recognition of N-glycans by several plant lectins, human galectins, influenza viruses, and Siglecs, and explored the influence of sialic acid linkages and branching of the N-glycans...
January 22, 2019: Cell Chemical Biology
Stefanie König, Simona Pace, Helmut Pein, Thorsten Heinekamp, Jan Kramer, Erik Romp, Maria Straßburger, Fabiana Troisi, Anna Proschak, Jan Dworschak, Kirstin Scherlach, Antonietta Rossi, Lidia Sautebin, Jesper Z Haeggström, Christian Hertweck, Axel A Brakhage, Jana Gerstmeier, Ewgenij Proschak, Oliver Werz
The epidithiodioxopiperazine gliotoxin is a virulence factor of Aspergillus fumigatus, the most important airborne fungal pathogen of humans. Gliotoxin suppresses innate immunity in invasive aspergillosis, particularly by compromising neutrophils, but the underlying molecular mechanisms remain elusive. Neutrophils are the first responders among innate immune cells recruited to sites of infection by the chemoattractant leukotriene (LT)B4 that is biosynthesized by 5-lipoxygenase and LTA4 hydrolase (LTA4 H). Here, we identified gliotoxin as inhibitor of LTA4 H that selectively abrogates LTB4 formation in human leukocytes and in distinct animal models...
January 17, 2019: Cell Chemical Biology
Hui Hong, Markiyan Samborskyy, Yongjun Zhou, Peter F Leadlay
Malayamycin A is an unusual bicyclic C-nucleoside, with interesting antiviral, antifungal, and anticancer bioactivity. We report here the discovery and characterization of the biosynthetic pathway to malayamycin by using genome mining of near-identical clusters both from the known producer Streptomyces malaysiensis and from Streptomyces chromofuscus. The key precursor 5'-pseudouridine monophosphate (5'-Ψ-MP) is supplied chiefly through the action of MalD, a TruD-like pseudouridine synthase. In vitro assays showed that MalO is an enoylpyruvyltransferase acting almost exclusively on 5'-Ψ-MP rather than 5'-UMP, while in contrast the counterpart enzyme NikO in the nikkomycin pathway readily accepts either substrate...
January 14, 2019: Cell Chemical Biology
Jeramie D Watrous, Teemu J Niiranen, Kim A Lagerborg, Mir Henglin, Yong-Jiang Xu, Jian Rong, Sonia Sharma, Ramachandran S Vasan, Martin G Larson, Aaron Armando, Samia Mora, Oswald Quehenberger, Edward A Dennis, Susan Cheng, Mohit Jain
Eicosanoids and related oxylipins are critical, small bioactive mediators of human physiology and inflammation. While ∼1,100 distinct species have been predicted to exist, to date, less than 150 of these molecules have been measured in humans, limiting our understanding of their role in human biology. Using a directed non-targeted mass spectrometry approach in conjunction with chemical networking of spectral fragmentation patterns, we find over 500 discrete chemical signals highly consistent with known and putative eicosanoids and related oxylipins in human plasma including 46 putative molecules not previously described...
January 11, 2019: Cell Chemical Biology
Yan Shi, Sajan Parag, Rekha Patel, Ashley Lui, Michel Murr, Jianfeng Cai, Niketa A Patel
Long noncoding RNA (lncRNA) are regulatory RNAs >200 nt. We previously showed that lncRNA GAS5 decreases significantly in serum of type 2 diabetes mellitus (T2DM) patients. Hence, we sought to decipher the molecular mechanisms underlying the role of GAS5 in T2DM in adipose tissue. Using CHIP-RIP, we demonstrate that GAS5 binds to promoter of insulin receptor to regulate its expression, and its depletion inhibits glucose uptake and insulin signaling. Toward stabilizing GAS5 levels in T2DM, we incorporated a strategy to limit the degradation of GAS5 by blocking the interaction of GAS5 and UPF1 with a small molecule identified using OBTC screening strategy...
January 9, 2019: Cell Chemical Biology
Yunsu Jang, Heyjin Son, Sang-Wook Lee, Wonseok Hwang, Seung-Ryoung Jung, Jo Ann W Byl, Neil Osheroff, Sanghwa Lee
Topoisomerase II cleaves DNA at preferred sequences with different efficiencies; however, the mechanism of cleavage site selection is not known. Here we used single-molecule fluorescence assays that monitor several critical steps of DNA-topoisomerase II interactions, including binding/dissociation, bending/straightening, and cleavage/religation, and reveal that the cleavage site is selected mainly during the bending step. Furthermore, despite the sensitivity of the bending rate to the DNA sequence, it is not an intrinsic property of the DNA itself...
December 26, 2018: Cell Chemical Biology
Lee M Booty, Justyna M Gawel, Filip Cvetko, Stuart T Caldwell, Andrew R Hall, John F Mulvey, Andrew M James, Elizabeth C Hinchy, Tracy A Prime, Sabine Arndt, Cristiane Beninca, Thomas P Bright, Menna R Clatworthy, John R Ferdinand, Hiran A Prag, Angela Logan, Julien Prudent, Thomas Krieg, Richard C Hartley, Michael P Murphy
Mitochondrial glutathione (GSH) and thioredoxin (Trx) systems function independently of the rest of the cell. While maintenance of mitochondrial thiol redox state is thought vital for cell survival, this was not testable due to the difficulty of manipulating the organelle's thiol systems independently of those in other cell compartments. To overcome this constraint we modified the glutathione S-transferase substrate and Trx reductase (TrxR) inhibitor, 1-chloro-2,4-dinitrobenzene (CDNB) by conjugation to the mitochondria-targeting triphenylphosphonium cation...
December 18, 2018: Cell Chemical Biology
Khuchtumur Bum-Erdene, Donghui Zhou, Giovanni Gonzalez-Gutierrez, Mona K Ghozayel, Yubing Si, David Xu, Harlan E Shannon, Barbara J Bailey, Timothy W Corson, Karen E Pollok, Clark D Wells, Samy O Meroueh
The Hippo pathway coordinates extracellular signals onto the control of tissue homeostasis and organ size. Hippo signaling primarily regulates the ability of Yap1 to bind and co-activate TEA domain (TEAD) transcription factors. Yap1 tightly binds to TEAD4 via a large flat interface, making the development of small-molecule orthosteric inhibitors highly challenging. Here, we report small-molecule TEAD⋅Yap inhibitors that rapidly and selectively form a covalent bond with a conserved cysteine located within the unique deep hydrophobic palmitate-binding pocket of TEADs...
December 18, 2018: Cell Chemical Biology
Mahmoud Hajj Chehade, Ludovic Pelosi, Cameron David Fyfe, Laurent Loiseau, Bérengère Rascalou, Sabine Brugière, Katayoun Kazemzadeh, Chau-Duy-Tam Vo, Lidia Ciccone, Laurent Aussel, Yohann Couté, Marc Fontecave, Frédéric Barras, Murielle Lombard, Fabien Pierrel
Ubiquinone (UQ) is a polyprenylated lipid that is conserved from bacteria to humans and is crucial to cellular respiration. How the cell orchestrates the efficient synthesis of UQ, which involves the modification of extremely hydrophobic substrates by multiple sequential enzymes, remains an unresolved issue. Here, we demonstrate that seven Ubi proteins form the Ubi complex, a stable metabolon that catalyzes the last six reactions of the UQ biosynthetic pathway in Escherichia coli. The SCP2 domain of UbiJ forms an extended hydrophobic cavity that binds UQ intermediates inside the 1-MDa Ubi complex...
December 17, 2018: Cell Chemical Biology
Tabea Schneidewind, Shobhna Kapoor, Guillaume Garivet, George Karageorgis, Rishikesh Narayan, Gloria Vendrell-Navarro, Andrey P Antonchick, Slava Ziegler, Herbert Waldmann
Small-molecule chemotypes with unexpected bioactivity may be identified by combining strategies built on the biological relevance of, e.g., natural products (NPs), such as biology-oriented synthesis, with principles that enable efficient coverage of chemical space, such as fragment-based compound design. Evaluation in target-agnostic phenotypic assays and target identification may link biologically relevant chemotypes to unexpected and unknown targets. We describe the phenotypic identification of an unprecedented kinase inhibitor chemotype obtained by synthetic combination of two biosynthetically unrelated NP fragment types...
December 11, 2018: Cell Chemical Biology
Leslie Magtanong, Pin-Joe Ko, Milton To, Jennifer Yinuo Cao, Giovanni C Forcina, Amy Tarangelo, Carl C Ward, Kevin Cho, Gary J Patti, Daniel K Nomura, James A Olzmann, Scott J Dixon
The initiation and execution of cell death can be regulated by various lipids. How the levels of environmental (exogenous) lipids impact cell death sensitivity is not well understood. We find that exogenous monounsaturated fatty acids (MUFAs) potently inhibit the non-apoptotic, iron-dependent, oxidative cell death process of ferroptosis. This protective effect is associated with the suppression of lipid reactive oxygen species (ROS) accumulation at the plasma membrane and decreased levels of phospholipids containing oxidizable polyunsaturated fatty acids...
December 11, 2018: Cell Chemical Biology
Sonya M Hanson, George Georghiou, Manish K Thakur, W Todd Miller, Joshua S Rest, John D Chodera, Markus A Seeliger
ATP-competitive kinase inhibitors often bind several kinases due to the high conservation of the ATP binding pocket. Through clustering analysis of a large kinome profiling dataset, we found a cluster of eight promiscuous kinases that on average bind more than five times more kinase inhibitors than the other 398 kinases in the dataset. To understand the structural basis of promiscuous inhibitor binding, we determined the co-crystal structure of the receptor tyrosine kinase DDR1 with the type I inhibitors dasatinib and VX-680...
December 11, 2018: Cell Chemical Biology
Yi-Jia Li, Li Du, Jianghai Wang, Ramir Vega, Terry D Lee, Yunan Miao, Grace Aldana-Masangkay, Eric R Samuels, Baozong Li, S Xiaohu Ouyang, Sharon A Colayco, Ekaterina V Bobkova, Daniela B Divlianska, Eduard Sergienko, Thomas D Y Chung, Marwan Fakih, Yuan Chen
Ubiquitin-like (Ubl) post-translational modifications are potential targets for therapeutics. However, the only known mechanism for inhibiting a Ubl-activating enzyme is through targeting its ATP-binding site. Here we identify an allosteric inhibitory site in the small ubiquitin-like modifier (SUMO)-activating enzyme (E1). This site was unexpected because both it and analogous sites are deeply buried in all previously solved structures of E1s of ubiquitin-like modifiers (Ubl). The inhibitor not only suppresses SUMO E1 activity, but also enhances its degradation in vivo, presumably due to a conformational change induced by the compound...
December 5, 2018: Cell Chemical Biology
Qing Ye, Yinan Zhang, Yanan Cao, Xiachang Wang, Yubin Guo, Jing Chen, Jamie Horn, Larissa V Ponomareva, Luksana Chaiswing, Khaled A Shaaban, Qiou Wei, Bradley D Anderson, Daret K St Clair, Haining Zhu, Markos Leggas, Jon S Thorson, Qing-Bai She
Peroxiredoxin 1 (Prx1) and glutaredoxin 3 (Grx3) are two major antioxidant proteins that play a critical role in maintaining redox homeostasis for tumor progression. Here, we identify the prototypical pyranonaphthoquinone natural product frenolicin B (FB) as a selective inhibitor of Prx1 and Grx3 through covalent modification of active-site cysteines. FB-targeted inhibition of Prx1 and Grx3 results in a decrease in cellular glutathione levels, an increase of reactive oxygen species (ROS), and concomitant inhibition of cancer cell growth, largely by activating the peroxisome-bound tuberous sclerosis complex to inhibit mTORC1/4E-BP1 signaling axis...
December 4, 2018: Cell Chemical Biology
Zhenzhen Liu, Hongli Li, Lian He, Yu Xiang, Chengsen Tian, Can Li, Peng Tan, Ji Jing, Yanpin Tian, Lupei Du, Yun Huang, Leng Han, Minyong Li, Yubin Zhou
Glioblastoma (GBM) is among the most common and malignant types of primary brain tumors in adults, with a dismal prognosis. Although alkylating agents such as temozolomide are widely applied as the first-line treatment for GBM, they often cause chemoresistance and remain ineffective with recurrent GBM. Alternative therapeutics against GBM are urgently needed in the clinic. We report herein the discovery of a class of inhibitors (YZ129 and its derivatives) of the calcineurin-NFAT pathway that exhibited potent anti-tumor activity against GBM...
November 30, 2018: Cell Chemical Biology
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