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Chemistry & Biology

Takashi Kawakami, Koji Ogawa, Naoki Goshima, Tohru Natsume
Polypeptide-tag/small-molecule pairs for specific cellular protein labeling are useful for visualizing cellular proteins and controlling their activity. Here, we report the development of an in vitro evolution-based (poly)peptide tag identification system named the DIVERSE (Directed In Vitro Evolution of Reactive peptide tags via Sequential Enrichment) system. In this system, an extremely diverse (10(14)) library of peptide tags, displayed by covalent attachment to their encoding cDNAs, is continuously prepared from the DNA library in a one-pot approach...
December 17, 2015: Chemistry & Biology
Virginia del Solar, Darleny Y Lizardo, Nasi Li, Jerod J Hurst, Christopher J Brais, G Ekin Atilla-Gokcumen
Apoptosis is accompanied by distinct morphological changes at the plasma and organelle membrane level. Involvement of certain lipids in apoptosis has been established; however, we have limited understanding of the specific lipid structures that participate in this process. We used untargeted comparative lipidomics to study the changes in lipid composition during staurosporine-induced apoptosis in HCT-116. Our results revealed that ceramides, dihydroceramides, and sphingomyelins, with defined acyl chains, constitute the majority of changes in the lipidome...
December 17, 2015: Chemistry & Biology
Thomas M Moon, Nathan R Tykocki, Jessica L Sheehe, Brent W Osborne, Werner Tegge, Joseph E Brayden, Wolfgang R Dostmann
PKG is a multifaceted signaling molecule and potential pharmaceutical target due to its role in smooth muscle function. A helix identified in the structure of the regulatory domain of PKG Iα suggests a novel architecture of the holoenzyme. In this study, a set of synthetic peptides (S-tides), derived from this helix, was found to bind to and activate PKG Iα in a cyclic guanosine monophosphate (cGMP)-independent manner. The most potent S-tide derivative (S1.5) increased the open probability of the potassium channel KCa1...
December 17, 2015: Chemistry & Biology
Mirella Vivoli, Michail N Isupov, Rebecca Nicholas, Andrew Hill, Andrew E Scott, Paul Kosma, Joann L Prior, Nicholas J Harmer
Gram-negative bacteria utilize heptoses as part of their repertoire of extracellular polysaccharide virulence determinants. Disruption of heptose biosynthesis offers an attractive target for novel antimicrobials. A critical step in the synthesis of heptoses is their 1-O phosphorylation, mediated by kinases such as HldE or WcbL. Here, we present the structure of WcbL from Burkholderia pseudomallei. We report that WcbL operates through a sequential ordered Bi-Bi mechanism, loading the heptose first and then ATP...
December 17, 2015: Chemistry & Biology
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Each month, Chemistry & Biology Select highlights a selection of research reports from the recent literature. These highlights are a snapshot of interesting research done across the field of chemical biology. Our December 2015 selection includes an insight into how vitamin C destroys cancer cells, a new method that makes possible the investigatation of sulfhydration, and the mapping of the CFTR interactome and how it depends on the environmental conditions and differs between wild-type and disease-causing mutant...
December 17, 2015: Chemistry & Biology
Moniek Riemersma, D Sean Froese, Walinka van Tol, Udo F Engelke, Jolanta Kopec, Monique van Scherpenzeel, Angel Ashikov, Tobias Krojer, Frank von Delft, Marco Tessari, Anna Buczkowska, Ewa Swiezewska, Lucas T Jae, Thijn R Brummelkamp, Hiroshi Manya, Tamao Endo, Hans van Bokhoven, Wyatt W Yue, Dirk J Lefeber
A unique, unsolved O-mannosyl glycan on α-dystroglycan is essential for its interaction with protein ligands in the extracellular matrix. Defective O-mannosylation leads to a group of muscular dystrophies, called dystroglycanopathies. Mutations in isoprenoid synthase domain containing (ISPD) represent the second most common cause of these disorders, however, its molecular function remains uncharacterized. The human ISPD (hISPD) crystal structure showed a canonical N-terminal cytidyltransferase domain linked to a C-terminal domain that is absent in cytidyltransferase homologs...
December 17, 2015: Chemistry & Biology
Eugene L Piatnitski Chekler, Jessica A Pellegrino, Thomas A Lanz, R Aldrin Denny, Andrew C Flick, Jotham Coe, Jonathan Langille, Arindrajit Basak, Shenping Liu, Ingrid A Stock, Parag Sahasrabudhe, Paul D Bonin, Kevin Lee, Mathew T Pletcher, Lyn H Jones
Bromodomains are involved in transcriptional regulation through the recognition of acetyl lysine modifications on diverse proteins. Selective pharmacological modulators of bromodomains are lacking, although the largely hydrophobic nature of the pocket makes these modules attractive targets for small-molecule inhibitors. This work describes the structure-based design of a highly selective inhibitor of the CREB binding protein (CBP) bromodomain and its use in cell-based transcriptional profiling experiments. The inhibitor downregulated a number of inflammatory genes in macrophages that were not affected by a selective BET bromodomain inhibitor...
December 17, 2015: Chemistry & Biology
Sheng Huang, Somayah Sameer Elsayed, Meinan Lv, Jioji Tabudravu, Mostafa E Rateb, Roland Gyampoh, Kwaku Kyeremeh, Rainer Ebel, Marcel Jaspars, Zixin Deng, Yi Yu, Hai Deng
Neocarazostatin A (NZS) is a bacterial alkaloid with promising bioactivities against free radicals, featuring a tricyclic carbazole nucleus with a prenyl moiety at C-6 of the carbazole ring. Here, we report the discovery and characterization of the biosynthetic pathway of NZS through genome mining and gene inactivation. The in vitro assays characterized two enzymes: NzsA is a P450 hydroxylase and NzsG is a new phytoene-synthase-like prenyltransferase (PTase). This is the first reported native PTase that specifically acts on the carbazole nucleus...
December 17, 2015: Chemistry & Biology
Zibo Zhao, Lu Wang, Taryn James, Youngeun Jung, Ikyon Kim, Renxiang Tan, F Michael Hoffmann, Wei Xu
ERβ is regarded as a "tumor suppressor" in breast cancer due to its anti-proliferative effects. However, unlike ERα, ERβ has not been developed as a therapeutic target in breast cancer due to loss of ERβ in aggressive cancers. In a small-molecule library screen for ERβ stabilizers, we identified Diptoindonesin G (Dip G), which significantly increases ERβ protein stability while decreasing ERα protein levels. Dip G enhances the transcription and anti-proliferative activities of ERβ, while attenuating the transcription and proliferative effects of ERα...
December 17, 2015: Chemistry & Biology
Sonali Srivastava, Sarika Chaudhary, Lipi Thukral, Ce Shi, Rinkoo D Gupta, Radhika Gupta, K Priyadarshan, Archana Vats, Asfarul S Haque, Rajan Sankaranarayanan, Vivek T Natarajan, Rakesh Sharma, Courtney C Aldrich, Rajesh S Gokhale
Mycobacterium tuberculosis (Mtb) can survive in hypoxic necrotic tissue by assimilating energy from host-derived fatty acids. While the expanded repertoire of β-oxidation auxiliary enzymes is considered crucial for Mtb adaptability, delineating their functional relevance has been challenging. Here, we show that the Mtb fatty acid degradation (FadAB) complex cannot selectively break down cis fatty acyl substrates. We demonstrate that the stereoselective binding of fatty acyl substrates in the Mtb FadB pocket is due to the steric hindrance from Phe287 residue...
December 17, 2015: Chemistry & Biology
Gabriel Ortega, Tammo Diercks, Oscar Millet
Halophilic organisms thrive in environments with extreme salt concentrations and have adapted by allowing molar quantities of cosolutes, mainly KCl, to accumulate in their cytoplasm. To cope with this high intracellular salinity, halophilic organisms modified the chemical composition of their proteins to enrich their surface with acidic and short polar side chains, while lysines and bulky hydrophobic residues got depleted. We have emulated the evolutionary process of haloadaptation with natural and designed halophilic polypeptides and applied novel nuclear magnetic resonance (NMR) methodology to study the different mechanisms contributing to protein haloadaptation at a per residue level...
December 17, 2015: Chemistry & Biology
Daria M Shcherbakova, Mikhail Baloban, Sergei Pletnev, Vladimir N Malashkevich, Hui Xiao, Zbigniew Dauter, Vladislav V Verkhusha
Near-infrared fluorescent proteins (NIR FPs) engineered from bacterial phytochromes (BphPs) are the probes of choice for deep-tissue imaging. Detection of several processes requires spectrally distinct NIR FPs. We developed an NIR FP, BphP1-FP, which has the most blue-shifted spectra and the highest fluorescence quantum yield among BphP-derived FPs. We found that these properties result from the binding of the biliverdin chromophore to a cysteine residue in the GAF domain, unlike natural BphPs and other BphP-based FPs...
November 19, 2015: Chemistry & Biology
Ahmed M Ali, Jakeb M Reis, Yan Xia, Asim J Rashid, Valentina Mercaldo, Brandon J Walters, Katherine E Brechun, Vitali Borisenko, Sheena A Josselyn, John Karanicolas, G Andrew Woolley
Current approaches for optogenetic control of transcription do not mimic the activity of endogenous transcription factors, which act at numerous sites in the genome in a complex interplay with other factors. Optogenetic control of dominant negative versions of endogenous transcription factors provides a mechanism for mimicking the natural regulation of gene expression. Here we describe opto-DN-CREB, a blue-light-controlled inhibitor of the transcription factor CREB created by fusing the dominant negative inhibitor A-CREB to photoactive yellow protein (PYP)...
November 19, 2015: Chemistry & Biology
Debasish Halder, Gyeong-Eon Chang, Debojyoti De, Eunji Cheong, Kyeong Kyu Kim, Injae Shin
Sox2 is a key player in the maintenance of pluripotency and stemness, and thus inhibition of its function would abrogate the stemness of pluripotent cells and induce differentiation into several types of cells. Herein we describe a strategy that relies on a combination of Sox2 inhibition with lineage-specific induction to promote efficient and selective differentiation of pluripotent P19 cells into neurons. When P19 cells transduced with Skp protein, an inhibitor of Sox2, are incubated with a neurogenesis inducer, the cells are selectively converted into neurons that generate depolarization-induced sodium currents and action potentials...
November 19, 2015: Chemistry & Biology
Charles Olea, Joachim Weidmann, Philip E Dawson, Gerald F Joyce
L-RNA aptamers were developed that bind to barnase RNase and thereby inhibit the function of the enzyme. These aptamers were obtained by first carrying out in vitro selection of D-RNAs that bind to the full-length synthetic D-enantiomer of barnase, then reversing the mirror and preparing L-RNAs of identical sequence that similarly bind to natural L-barnase. The resulting L-aptamers bind L-barnase with an affinity of ∼100 nM and function as competitive inhibitors of enzyme cleavage of D-RNA substrates. L-RNA aptamers are resistant to degradation by ribonucleases, thus enabling them to function in biological samples, most notably for applications in molecular diagnostics and therapeutics...
November 19, 2015: Chemistry & Biology
Milka Kostic
Each month, Chemistry & Biology Select highlights a selection of research reports from the recent literature. These highlights are a snapshot of interesting research done across the field of chemical biology. Our November 2015 selection includes an insight into non-overlapping biosynthetic pathways that lead to formation of Mycobacterium tuberculosis peptidoglycan, a new method to not only measure but also buffer the endosomal pH using nanoparticles, and a demonstration that non-coding RNAs can be a target for antibiotic discovery...
November 19, 2015: Chemistry & Biology
Thomas M Charlton, Andrea Kovacs-Simon, Stephen L Michell, Neil F Fairweather, Edward W Tate
Bacterial lipoproteins are surface exposed, anchored to the membrane by S-diacylglyceryl modification of the N-terminal cysteine thiol. They play important roles in many essential cellular processes and in bacterial pathogenesis. For example, Clostridium difficile is a Gram-positive anaerobe that causes severe gastrointestinal disease; however, its lipoproteome remains poorly characterized. Here we describe the application of metabolic tagging with alkyne-tagged lipid analogs, in combination with quantitative proteomics, to profile protein lipidation across diverse C...
November 19, 2015: Chemistry & Biology
Jiaxin Hu, Jing Liu, Liande Li, Keith T Gagnon, David R Corey
A GGGGCC expansion within an intronic region of the C9orf72 gene forms RNA foci that are associated with one-third of familial amyotrophic lateral sclerosis and one-quarter of frontotemporal dementia. The C9orf72 locus also expresses an antisense transcript with a CCCCGG expansion that forms foci and may contribute to disease. Synthetic agents that bind these hexanucleotide repeats and block foci would be leads for therapeutic discovery. We have engineered duplex RNAs to enable them to recognize difficult C/G targets...
November 19, 2015: Chemistry & Biology
Romila D Gopalan, Mark P Del Borgo, Adam I Mechler, Patrick Perlmutter, Marie-Isabel Aguilar
Peptides comprised entirely of β-amino acids, or β-peptides, have attracted substantial interest over the past 25 years due to their unique structural and chemical characteristics. β-Peptides form well-defined secondary structures that exhibit different geometries compared with their α-peptide counterparts, giving rise to their foldamer classification. β-Peptide foldamers can be functionalized easily and are metabolically stable and, together with the predictable side-chain topography, have led to the design of a growing number of bioactive β-peptides with a range of biological targets...
November 19, 2015: Chemistry & Biology
Carole Urbach, Nathaniel C Gordon, Ian Strickland, David Lowne, Cathy Joberty-Candotti, Richard May, Athula Herath, DirkJan Hijnen, Judith L Thijs, Carla A Bruijnzeel-Koomen, Ralph R Minter, Florian Hollfelder, Lutz Jermutus
The practical realization of disease modulation by catalytic degradation of a therapeutic target protein suffers from the difficulty to identify candidate proteases, or to engineer their specificity. We identified 23 measurable, specific, and new protease activities using combinatorial screening of 27 human proteases against 24 therapeutic protein targets. We investigate the cleavage of monocyte chemoattractant protein 1, interleukin-6 (IL-6), and IL-13 by matrix metalloproteinases (MMPs) and serine proteases, and demonstrate that cleavage of IL-13 leads to potent inhibition of its biological activity in vitro...
November 19, 2015: Chemistry & Biology
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