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ACS Chemical Biology

Theodore J Zwang, Edmund C M Tse, Jacqueline K Barton
DNA charge transport chemistry involves the migration of charge over long molecular distances through the aromatic base pair stack within the DNA helix. This migration depends upon the intimate coupling of bases stacked one with another, and hence any perturbation in that stacking, through base modifications or protein binding, can be sensed electrically. In this review we describe the many ways DNA charge transport chemistry has been utilized to sense changes in DNA including the presence of lesions, mismatches, DNA-binding proteins, protein activity, and even reactions under weak magnetic fields...
May 23, 2018: ACS Chemical Biology
Acacia F Dishman, Brian F Volkman
Since the proposal of Anfinsen's thermodynamic hypothesis in 1963, our understanding of protein folding and dynamics has gained significant appreciation of its nuance and complexity. Intrinsically disordered proteins, chameleonic sequences, morpheeins, and metamorphic proteins have broadened the protein folding paradigm. Here, we discuss noncanonical protein folding patterns, with an emphasis on metamorphic proteins, and we review known metamorphic proteins that occur naturally and that have been engineered in the laboratory...
May 22, 2018: ACS Chemical Biology
Sneha Ray, Dale F Kreitler, Andrew M Gulick, Andrew S Murkin
We report the unprecedented reaction between a nitroalkane and an active-site cysteine residue to yield a thiohydroximate adduct. Structural and kinetic evidence suggests the nitro group is activated by conversion to its nitronic acid tautomer within the active site. The nitro group, therefore, shows promise as a masked electrophile in the design of covalent inhibitors targeting binding pockets with appropriately placed cysteine and general acid residues.
May 21, 2018: ACS Chemical Biology
Zhaojun Yin, Xuanjun Wu, Katarzyna Kaczanowska, Suttipun Sungsuwan, Marta Comellas-Aragones, Christian Pett, Jin Yu, Claire Baniel, Ulrika Westerlind, M G Finn, Xuefei Huang
Mucin-1 (MUC1) is one of the top ranked tumor associated antigens. In order to generate effective anti-MUC1 immune responses as potential anti-cancer vaccines, MUC1 peptides and glycopeptides have been covalently conjugated to bacteriophage Qb. Immunization of mice with these constructs led to highly potent antibody responses with IgG titers over one million, which are among the highest anti-MUC1 IgG titers reported to date. Furthermore, the high IgG antibody levels persisted for more than six months. The constructs also elicited MUC1 specific cytotoxic T cells, which can selectively kill MUC1 positive tumor cells...
May 21, 2018: ACS Chemical Biology
Toshiyuki Taniyama, Natsumi Tsuda, Shinji Sueda
The nuclear envelope (NE) is a double membrane that segregates nuclear components from the cytoplasm in eukaryote cells. It is well-known that the NE undergoes a breakdown and reformation during mitosis in animal cells. However, the detailed mechanisms of the NE dynamics are not yet fully understood. Here, we propose a method for the fluorescent labeling of the NE in living cells, which enables the tracing of the NE dynamics during cell division under physiological conditions. In our method, labeling of the NE is accomplished by fixing green fluorescent protein carrying the nuclear localization signal on the inner nuclear membrane based on a unique biotinylation reaction from the archaeon Sulfolobus tokodaii...
May 21, 2018: ACS Chemical Biology
Vaibhav Bhandari, Keith S Wong, Jin Lin Zhou, Mark F Mabanglo, Robert A Batey, Walid A Houry
In prokaryotic cells and eukaryotic organelles, the ClpP protease plays an important role in proteostasis. The disruption of ClpP function has been shown to influence the infectivity and virulence of a number of bacterial pathogens. More recently, ClpP has been found to be involved in various forms of carcinomas and in Perrault syndrome, which is an inherited condition characterized by hearing loss in males and females and by ovarian abnormalities in females. Hence, targeting ClpP is a potentially viable, attractive option for the treatment of different ailments...
May 18, 2018: ACS Chemical Biology
Alshaimaa A Elgarf, David C B Siebert, Friederike Steudle, Angelika Draxler, Guanguan Li, Shengming Huang, James M Cook, Margot Ernst, Petra Scholze
Benzodiazepines are clinically relevant drugs, which bind to GABAA neurotransmitter receptors at the α+/γ2- interfaces and thereby enhance GABA induced chloride ion flux leading to neuronal hyperpolarization. However, the structural basis of benzodiazepine interactions with their high affinity site at GABAA receptors is controversially debated in the literature and in silico studies led to discrepant binding mode hypotheses. In the current study computational docking of diazepam into α+/γ2- homology models suggested that a chiral methyl group, which is known to promote preferred binding to α5-containing GABAA receptors (position 3 of the 7-membered diazepine ring), could possibly provide experimental evidence in favor of or against the so far proposed binding modes...
May 16, 2018: ACS Chemical Biology
Mark C Weir, Sherry T Shu, Ravi K Patel, Sabine Hellwig, Li Chen, Li Tan, Nathanael S Gray, Thomas E Smithgall
Acute myelogenous leukemia (AML) is the most common hematologic malignancy in adults, and is often associated with constitutive tyrosine kinase signaling. These pathways involve the non-receptor tyrosine kinases Fes, Syk and the three Src-family kinases expressed in myeloid cells (Fgr, Hck, and Lyn). In this study, we report remarkable anti-AML efficacy of an N-phenylbenzamide kinase inhibitor, TL02-59. This compound potently suppressed the proliferation of bone marrow samples from twenty of twenty-six AML patients, with a striking correlation between inhibitor sensitivity and expression levels of the myeloid Src family kinases Fgr, Hck, and Lyn...
May 15, 2018: ACS Chemical Biology
Khaled H Almabruk, Linh K Dinh, Benjamin Philmus
Microorganisms are prolific producers of bioactive natural products with an array of biological activities and impact on human and animal health. But with great power comes great responsibility and the organisms that produce a bioactive compound must be resistant to its biological effects to survive during production/accumulation. Microorganism, particularly bacteria, have developed different strategies to prevent self-toxicity. Here we review a few of the major mechanisms including mechanism of resistance with a focus on self-resistant protein variants, target proteins that contain amino acid substitutions to reduce the binding of the bioactive natural product and therefore its inhibitory effect are highlighted in depth...
May 15, 2018: ACS Chemical Biology
Maximilian Frey, Katharina Schmauder, Irini Pateraki, Otmar Spring
Sesquiterpene lactones are a class of natural compounds well-known for their bioactivity and are characteristic for the Asteraceae family. Most sesquiterpene lactones are considered derivatives of germacrene A acid (GAA). GAA can be stereo-specifically hydroxylated by the cytochrome P450 enzymes (CYP) Lactuca sativa costunolide synthase CYP71BL2 (LsCOS) and Helianthus annuus GAA 8-hydroxylase CYP71BL1 (HaG8H) at C6 (in -orientation) or C8 (in -orientation), respectively. Spontaneous subsequent lactonization of the resulting 6-hydroxy-GAA leads to costunolide, whereas 8-hydroxy-GAA has not yet been reported to cyclize to a sesquiterpene lactone...
May 14, 2018: ACS Chemical Biology
Shun-Ichi Tanaka, Tetsuya Takahashi, Akiko Koide, Riki Iwamoto, Satoshi Koikeda, Shohei Koide
Controlling catalytic properties of enzymes remain an important challenge in chemistry and biotechnology. We have recently established a strategy for altering enzyme specificity in which the addition of proxy monobodies, synthetic binding proteins, modulates the specificity of an otherwise unmodified enzyme. Here, in order to examine its broader applicability we employed the strategy on Candida rugosa lipase 1 (CRL1), an enzyme with a tunnel-like substrate binding site. We successfully identified proxy monobodies that restricted the substrate specificity of CRL1 toward short-chain fatty acids...
May 14, 2018: ACS Chemical Biology
Maria Romano, Giuliana Fusco, Hassanul G Choudhury, Shahid Mehmood, Carol V Robinson, Séverine Zirah, Julian D Hegemann, Ewen Lescop, Mohamed A Marahiel, Sylvie Rebuffat, Alfonso De Simone, Konstantinos Beis
Bacteria under stress produce ribosomally synthesized and posttranslationally modified peptides (RiPPs) to target closely related species, such as the lasso peptide microcin J25 (MccJ25). These peptides are also toxic to the producing organisms that utilize dedicated ABC transporters to achieve self-immunity. MccJ25 is exported by the Escherichia coli ABC transporter McjD through a complex mechanism of recognition that has remained elusive. Here, we used biomolecular NMR to study this interaction and identified a region of the toxic peptide that is crucial to its recognition by the ABC transporter...
May 14, 2018: ACS Chemical Biology
Nagaraja Mukkayyan, Deepti Sharan, Parthasarathi Ajitkumar
Diadenosine polyphosphates, Ap(2-7)A, which contain two adenosines in a 5',5' linkage through phosphodiester bonds involving 2-7 phosphates, regulate diverse cellular functions in all the organisms, from bacteria to humans, under normal and stress conditions. We had earlier reported consistent occurrence of asymmetric constriction during division (ACD) in 20-30% of dividing mycobacterial cells in culture, irrespective of different growth media, implying exogenous action of some factor of mycobacterial origin...
May 14, 2018: ACS Chemical Biology
Charles W Hespen, Joel J Bruegger, Yirui Guo, Michael A Marletta
Heme nitric oxide/oxygen sensing (H-NOX) domains are direct NO sensors that regulate a variety of biological functions in both bacteria and eukaryotes. Previous work on H-NOX proteins has shown that upon NO binding, a conformational change occurs along two glycine residues on adjacent helices (termed the glycine hinge). Despite the apparent importance of the glycine hinge, it is not fully conserved in all H-NOX domains. Several H-NOX sensors from the family Flavobacteriaceae contain a native alanine substitution in one of the hinge residues...
May 14, 2018: ACS Chemical Biology
Kim Nguyen, Mahima B Aggarwal, Chao Feng, Gabriela Balderrama, Michael Fazio, Ali Mortazavi, Robert C Spitale
The cellular RNA pool in animals arises from two separate genomes stored in the nucleus and multiple mitochondria. Chemical methods to track nascent RNA syntheses are unable to distinguish between these two with stringency. Herein we report that spatially restricting bioorthogonal nucleoside biosynthesis enables, for the first time, selective metabolic labeling of the RNA transcribed in the mitochondria. We envision this approach could open the door for heretofore-impossible analyses of mitochondrial RNA. Beyond our results revealed herein, our approach provides a roadmap for researchers to begin to design strategies to examine biomolecules within subcellular compartments...
May 14, 2018: ACS Chemical Biology
Mahsa Sadeghi, Bodil B Carstens, Brid P Callaghan, James T Daniel, Han Shen Tae, Tracey O'Donnell, Joel Castro, Stuart M Brierley, David J Adams, David J Craik, Richard J Clark
α-Conotoxins are disulfide-bonded peptides from cone snail venoms and are characterized by their affinity for nicotinic acetylcholine receptors (nAChR). Several α-conotoxins with distinct selectivity for nAChR subtypes have been identified as potent analgesics in animal models of chronic pain. However, a number of α-conotoxins have been shown to inhibit N-type calcium channel currents in rodent dissociated dorsal root ganglion (DRG) neurons via activation of G protein-coupled GABAB receptors (GABABR). Therefore it is unclear whether activation of GABABR or inhibition of α9α10 nAChRs is the analgesic mechanism...
May 10, 2018: ACS Chemical Biology
Charuta C Palsuledesai, Zurab Surviladze, Anna Waller, T Fabiola Miscioscia, Yuna Guo, Yang Wu, Jake Strouse, Elsa Romero, Virginia M Salas, Ramona Curpan, Susan Young, Mark Carter, Terry Foutz, Zhanna Galochkina, Harold Ames, Mark K Haynes, Bruce S Edwards, Orazio Nicolotti, Li Luo, Oleg Ursu, Cristian G Bologa, Tudor I Oprea, Angela Wandinger-Ness, Larry A Sklar
Ras and Ras-related small GTPases are key regulators of diverse cellular functions that impact cell growth, survival, motility, morphogenesis and differentiation. They are important targets for studies of disease mechanisms as well as drug discovery. Here, we report the characterization of small molecule agonists of one or more of six Rho, Rab and Ras family GTPases that were first identified through flow cytometry based, multi-plexed high throughput screening of 200,000 compounds. The activators were categorized into three distinct chemical families that are represented by three lead compounds having the highest activity...
May 10, 2018: ACS Chemical Biology
Alyssa N Preston, Joshua D Farr, Brianna K O'Neill, Kaitlyn K Thompson, Stella E Tsirka, Scott T Laughlin
Astrocytes are the most abundant cells in the brain. They support neurons, adjust synaptic strength, and modulate neuronal signaling, yet the full extent of their functions is obscured by the dearth of methods for their visualization and analysis. Here, we report a chemical reporter that targets small molecules specifically to astrocytes both in vitro and in vivo. Fluorescent versions of this tag are imported through an organic cation transporter to label glia across species. The structural modularity of this approach will enable wide-ranging applications for understanding astrocyte biology...
May 9, 2018: ACS Chemical Biology
Xing Zhang, Ke Xia, Lei Lin, Fuming Zhang, Yanlei Yu, Kalib St Ange, Xiaorui Han, Eric Edsinger, Joel Sohn, Robert J Linhardt
The skate, a cartilaginous fish related to sharks and rays, possesses a unique electrosensitive sensory organ known as the ampullae of Lorenzini (AoL). This organ is responsible for the detection of weak electric field changes caused by the muscle contractions of their prey. While keratan sulfate (KS) is believed to be a component of a jelly that fills this sensory organ and has been credited with its high proton conductivity, modern analytical methods have not been applied to its characterization. Surprisingly, total glycosaminoglycan (GAG) analysis demonstrates that the KS from skate jelly is extraordinarily pure, containing no other GAGs...
May 9, 2018: ACS Chemical Biology
María Georgina Herrera, María Florencia Pignataro, Martín Ezequiel Noguera, Karen Magalí Cruz, Javier Santos
Iron-sulfur clusters are essential cofactors in many biochemical processes. ISD11, one of the subunits of the protein complex that carries out the cluster assembly in mitochondria, is necessary for cysteine desulfurase NFS1 stability and function. Several authors have recently provided evidence showing that ISD11 interacts with the acyl carrier protein (ACP). We carried out the coexpression of human mitochondrial ACP and ISD11 in E. coli. This work shows that ACP and ISD11 form a soluble, structured and stable complex able to bind to the human NFS1 subunit modulating its activity...
May 8, 2018: ACS Chemical Biology
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