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Cell Chemical Biology

Jan M Falcke, Neelanjan Bose, Alexander B Artyukhin, Christian Rödelsperger, Gabriel V Markov, Joshua J Yim, Dominik Grimm, Marc H Claassen, Oishika Panda, Joshua A Baccile, Ying K Zhang, Henry H Le, Dino Jolic, Frank C Schroeder, Ralf J Sommer
In the nematodes Caenorhabditis elegans and Pristionchus pacificus, a modular library of small molecules control behavior, lifespan, and development. However, little is known about the final steps of their biosynthesis, in which diverse building blocks from primary metabolism are attached to glycosides of the dideoxysugar ascarylose, the ascarosides. We combine metabolomic analysis of natural isolates of P. pacificus with genome-wide association mapping to identify a putative carboxylesterase, Ppa-uar-1, that is required for attachment of a pyrimidine-derived moiety in the biosynthesis of ubas#1, a major dauer pheromone component...
May 14, 2018: Cell Chemical Biology
Salvador Guardiola, Roger Prades, Laura Mendieta, Arwin J Brouwer, Jelle Streefkerk, Laura Nevola, Teresa Tarragó, Rob M J Liskamp, Ernest Giralt
Prolyl oligopeptidase (POP), a serine protease highly expressed in the brain, has recently emerged as an enticing therapeutic target for the treatment of cognitive and neurodegenerative disorders. However, most reported inhibitors suffer from short duration of action, poor protease selectivity, and low blood-brain barrier (BBB) permeability, which altogether limit their potential as drugs. Here, we describe the structure-based design of the first irreversible, selective, and brain-permeable POP inhibitors. At low-nanomolar concentrations, these covalent peptidomimetics produce a fast, specific, and sustained inactivation of POP, both in vitro and in human cells...
May 7, 2018: Cell Chemical Biology
Theresa Kriegler, Anastasia Magoulopoulou, Rocio Amate Marchal, Tara Hessa
Secretory proteins translocate across the mammalian ER membrane co-translationally via the ribosome-sec61 translocation machinery. Signal sequences within the polypeptide, which guide this event, are diverse in their hydrophobicity, charge, length, and amino acid composition. Despite the known sequence diversity in the ER signals, it is generally assumed that they have a dominant role in determining co-translational targeting and translocation process. We have analyzed co-translational events experienced by secretory proteins carrying efficient versus inefficient signal sequencing, using an assay based on Xbp1 peptide-mediated translational arrest...
May 3, 2018: Cell Chemical Biology
Toby Passioura, Koichi Watashi, Kento Fukano, Satomi Shimura, Wakana Saso, Ryo Morishita, Yuki Ogasawara, Yasuhito Tanaka, Masashi Mizokami, Camille Sureau, Hiroaki Suga, Takaji Wakita
Hepatitis B virus (HBV) constitutes a significant public health burden, and currently available treatment options are not generally curative, necessitating the development of new therapeutics. Here we have applied random non-standard peptide integrated discovery (RaPID) screening to identify small macrocyclic peptide inhibitors of HBV entry that target the cell-surface receptor for HBV, sodium taurocholate cotransporting polypeptide (NTCP). In addition to their anti-HBV activity, these molecules also inhibit cellular entry by the related hepatitis D virus (HDV), and are active against diverse strains of HBV (including clinically relevant nucleos(t)ide analog-resistant and vaccine escaping strains)...
May 2, 2018: Cell Chemical Biology
Andrew D Lawrence, Emi Nemoto-Smith, Evelyne Deery, Joseph A Baker, Susanne Schroeder, David G Brown, Jennifer M A Tullet, Mark J Howard, Ian R Brown, Alison G Smith, Helena I Boshoff, Clifton E Barry, Martin J Warren
Vitamin B12 is made by only certain prokaryotes yet is required by a number of eukaryotes such as mammals, fish, birds, worms, and Protista, including algae. There is still much to learn about how this nutrient is trafficked across the domains of life. Herein, we describe ways to make a number of different corrin analogs with fluorescent groups attached to the main tetrapyrrole-derived ring. A further range of analogs were also constructed by attaching similar fluorescent groups to the ribose ring of cobalamin, thereby generating a range of complete and incomplete corrinoids to follow uptake in bacteria, worms, and plants...
April 28, 2018: Cell Chemical Biology
Elvira Sondo, Federico Falchi, Emanuela Caci, Loretta Ferrera, Elisa Giacomini, Emanuela Pesce, Valeria Tomati, Sine Mandrup Bertozzi, Luca Goldoni, Andrea Armirotti, Roberto Ravazzolo, Andrea Cavalli, Nicoletta Pedemonte
In cystic fibrosis (CF), deletion of phenylalanine 508 (F508del) in the CFTR channel is associated with misfolding and premature degradation of the mutant protein. Among the known proteins associated with F508del-CFTR processing, the ubiquitin ligase RNF5/RMA1 is particularly interesting. We previously demonstrated that genetic suppression of RNF5 in vivo leads to an attenuation of intestinal pathological phenotypes in CF mice, validating the relevance of RNF5 as a drug target for CF. Here, we used a computational approach, based on ligand docking and virtual screening, to discover inh-02, a drug-like small molecule that inhibits RNF5...
April 26, 2018: Cell Chemical Biology
Verónica Gordo, David Aparicio, Rosa Pérez-Luque, Antoni Benito, Maria Vilanova, Isabel Usón, Ignacio Fita, Marc Ribó
Split inteins are expressed as two separated subunits (N-intein and C-intein) fused to the corresponding exteins. The specific association of both intein subunits precedes protein splicing, which results in excision of the intein subunits and in ligation, by a peptide bond, of the concomitant exteins. Catalytically active intein precursors are typically too reactive for crystallization or even isolation. Neq pol is the trans-intein of the B-type DNA polymerase I split gene from hyperthermophile Nanoarchaeum equitans...
April 25, 2018: Cell Chemical Biology
Carlos Moreno-Yruela, Iacopo Galleano, Andreas S Madsen, Christian A Olsen
Histone deacetylase (HDAC) enzymes regulate diverse biological function, including gene expression, rendering them potential targets for intervention in a number of diseases, with a handful of compounds approved for treatment of certain hematologic cancers. Among the human zinc-dependent HDACs, the most recently discovered member, HDAC11, is the only member assigned to subclass IV. It is the smallest protein and has the least well understood biological function. Here, we show that HDAC11 cleaves long-chain acyl modifications on lysine side chains with remarkable efficiency...
April 23, 2018: Cell Chemical Biology
Julie K L Sinclair, Allison S Walker, Amy E Doerner, Alanna Schepartz
Epidermal growth factor receptor (EGFR) interacts through its extracellular domain with seven different growth factors. These factors induce different structures within the cytoplasmic juxtamembrane (JM) segment of the dimeric receptor and propagate different growth factor-dependent signals to the cell interior. How this process occurs is unknown. Here we apply diverse experimental and computational tools to show that growth factor identity is encoded by the EGFR transmembrane (TM) helix into discrete helix dimer populations that differ in both cross-location and cross-angle...
April 21, 2018: Cell Chemical Biology
Bastian Vögeli, Kyra Geyer, Patrick D Gerlinger, Sarah Benkstein, Niña Socorro Cortina, Tobias J Erb
The incorporation of different extender units generates structural diversity in polyketides. There is significant interest in engineering substrate specificity of polyketide synthases (PKSs) to change their chemical structure. Efforts to change extender unit selectivity are hindered by the lack of simple screening methods and easily available atypical extender units. Here, we present a chemo-biosynthetic strategy that employs biocatalytic proofreading and allows access to a large variety of extender units...
April 21, 2018: Cell Chemical Biology
Alok Pandey, Jayashree Pain, Nathaniel Dziuba, Ashutosh K Pandey, Andrew Dancis, Paul A Lindahl, Debkumar Pain
In eukaryotes, mitochondria have been hypothesized to generate sulfur species required for tRNA thiolation in the cytosol, although no direct evidence thus far exists. Here we have detected these sulfur species, making use of our observation that isolated yeast cytosol alone is unable to thiolate tRNAs but can do so upon addition of mitochondria. Mitochondria were found to utilize the cysteine desulfurase Nfs1 to produce sulfur-containing species with masses ranging from 700 to 1,100 Da. Mitochondria exported these species via the Atm1 transporter in the inner membrane...
April 21, 2018: Cell Chemical Biology
Nicole Merten, Julia Fischer, Katharina Simon, Liguo Zhang, Ralf Schröder, Lucas Peters, Anne-Gaelle Letombe, Stephanie Hennen, Ramona Schrage, Theresa Bödefeld, Celine Vermeiren, Michel Gillard, Klaus Mohr, Qing Richard Lu, Oliver Brüstle, Jesus Gomeza, Evi Kostenis
Identification of additional uses for existing drugs is a hot topic in drug discovery and a viable alternative to de novo drug development. HAMI3379 is known as an antagonist of the cysteinyl-leukotriene CysLT2 receptor, and was initially developed to treat cardiovascular and inflammatory disorders. In our study we identified HAMI3379 as an antagonist of the orphan G protein-coupled receptor GPR17. HAMI3379 inhibits signaling of recombinant human, rat, and mouse GPR17 across various cellular backgrounds, and of endogenous GPR17 in primary rodent oligodendrocytes...
April 18, 2018: Cell Chemical Biology
Taehyung C Lee, Crystal R Moran, Philip A Cistrone, Philip E Dawson, Ashok A Deniz
Single-molecule fluorescence is widely used to study conformational complexity in proteins, and has proven especially valuable with intrinsically disordered proteins (IDPs). Protein studies using dual-color single-molecule Förster resonance energy transfer (smFRET) are now quite common, but many could benefit from simultaneous measurement of multiple distances through multi-color labeling. Such studies, however, have suffered from limitations in site-specific incorporation of more than two dyes per polypeptide...
April 12, 2018: Cell Chemical Biology
Lunxi Liang, Huanbin Wang, Hubing Shi, Zhaoli Li, Han Yao, Zhigao Bu, Ningning Song, Chushu Li, Dabin Xiang, Yao Zhang, Jilin Wang, Ye Hu, Qi Xu, Yanlei Ma, Zhongyi Cheng, Yingchao Wang, Shuliang Zhao, Jin Qian, Yingxuan Chen, Jing-Yuan Fang, Jie Xu
Many cancer-related proteins are controlled by composite post-translational modifications (PTMs), but prevalent strategies only target one type of modification. Here we describe a designed peptide that controls two types of modifications of the p53 tumor suppressor, based on the discovery of a protein complex that suppresses p53 (suppresome). We found that Morn3, a cancer-testis antigen, recruits different PTM enzymes, such as sirtuin deacetylase and ubiquitin ligase, to confer composite modifications on p53...
April 10, 2018: Cell Chemical Biology
Euan Pyle, Antreas C Kalli, Sotiris Amillis, Zoe Hall, Andy M Lau, Aylin C Hanyaloglu, George Diallinas, Bernadette Byrne, Argyris Politis
The role of membrane lipids in modulating eukaryotic transporter assembly and function remains unclear. We investigated the effect of membrane lipids in the structure and transport activity of the purine transporter UapA from Aspergillus nidulans. We found that UapA exists mainly as a dimer and that two lipid molecules bind per UapA dimer. We identified three phospholipid classes that co-purified with UapA: phosphatidylcholine, phosphatidylethanolamine (PE), and phosphatidylinositol (PI). UapA delipidation caused dissociation of the dimer into monomers...
April 10, 2018: Cell Chemical Biology
Kevin R W Ngoei, Christopher G Langendorf, Naomi X Y Ling, Ashfaqul Hoque, Swapna Johnson, Michelle C Camerino, Scott R Walker, Ylva E Bozikis, Toby A Dite, Ashley J Ovens, William J Smiles, Roxane Jacobs, He Huang, Michael W Parker, John W Scott, Mark H Rider, Richard C Foitzik, Bruce E Kemp, Jonathan B Baell, Jonathan S Oakhill
The AMP-activated protein kinase (AMPK) αβγ heterotrimer regulates cellular energy homeostasis with tissue-specific isoform distribution. Small-molecule activation of skeletal muscle α2β2 AMPK complexes may prove a valuable treatment strategy for type 2 diabetes and insulin resistance. Herein, we report the small-molecule SC4 is a potent, direct AMPK activator that preferentially activates α2 complexes and stimulates skeletal muscle glucose uptake. In parallel with the term secretagog, we propose "importagog" to define a substance that induces or augments cellular uptake of another substance...
April 7, 2018: Cell Chemical Biology
Malvika Koundinya, Judith Sudhalter, Albane Courjaud, Bruno Lionne, Gaetan Touyer, Luc Bonnet, Isabelle Menguy, Isabelle Schreiber, Christelle Perrault, Stephanie Vougier, Brigitte Benhamou, Bailin Zhang, Timothy He, Qiang Gao, Patricia Gee, Daniel Simard, M Paola Castaldi, Ronald Tomlinson, Stephan Reiling, Matthieu Barrague, Richard Newcombe, Hui Cao, Yanjun Wang, Fangxian Sun, Joshua Murtie, Mark Munson, Eric Yang, David Harper, Monsif Bouaboula, Jack Pollard, Claudine Grepin, Carlos Garcia-Echeverria, Hong Cheng, Francisco Adrian, Christopher Winter, Stuart Licht, Ivan Cornella-Taracido, Rosalia Arrebola, Aaron Morris
Activating KRAS mutations are major oncogenic drivers in multiple tumor types. Synthetic lethal screens have previously been used to identify targets critical for the survival of KRAS mutant cells, but their application to drug discovery has proven challenging, possibly due in part to a failure of monolayer cultures to model tumor biology. Here, we report the results of a high-throughput synthetic lethal screen for small molecules that selectively inhibit the growth of KRAS mutant cell lines in soft agar. Chemoproteomic profiling identifies the target of the most KRAS-selective chemical series as dihydroorotate dehydrogenase (DHODH)...
April 3, 2018: Cell Chemical Biology
Qingfei Zheng, Yukang Gong, Yujiao Guo, Zhixiong Zhao, Zhuhua Wu, Zixuan Zhou, Dandan Chen, Lifeng Pan, Wen Liu
Here, we provide structural insights into PyrE3, a flavin-dependent [4 + 2] cyclase that catalyzes trans-decalin formation in the biosynthesis of pyrroindomycins. PyrE3 shares an architecture/domain organization head-to-tail similarity with the members of the family of para-hydroxybenzoate hydroxylase (pHBH)-fold monooxygenases, and possesses a flavin adenine dinucleotide (FAD)-binding domain, a middle domain, and a C-terminal thioredoxin-like domain. The FAD-binding domain forms a central hub of the protein structure, and binds with FAD in a "closed" conformation of pHBH-fold family monooxygenases known for their highly dynamic catalytic processes...
April 2, 2018: Cell Chemical Biology
Maria Jonson, Sofie Nyström, Alexander Sandberg, Marcus Carlback, Wojciech Michno, Jörg Hanrieder, Annika Starkenberg, K Peter R Nilsson, Stefan Thor, Per Hammarström
The basis for selective vulnerability of certain cell types for misfolded proteins (MPs) in neurodegenerative diseases is largely unknown. This knowledge is crucial for understanding disease progression in relation to MPs spreading in the CNS. We assessed this issue in Drosophila by cell-specific expression of human Aβ1-42 associated with Alzheimer's disease. Expression of Aβ1-42 in various neurons resulted in concentration-dependent severe neurodegenerative phenotypes, and intraneuronal ring-tangle-like aggregates with immature fibril properties when analyzed by aggregate-specific ligands...
April 2, 2018: Cell Chemical Biology
Mehmet Gundogdu, Salomé Llabrés, Andrii Gorelik, Andrew T Ferenbach, Ulrich Zachariae, Daan M F van Aalten
O-linked β-N-acetyl-D -glucosamine (O-GlcNAc) transferase (OGT) regulates protein O-GlcNAcylation, an essential post-translational modification that is abundant in the brain. Recently, OGT mutations have been associated with intellectual disability, although it is not understood how they affect OGT structure and function. Using a multi-disciplinary approach we show that the L254F OGT mutation leads to conformational changes of the tetratricopeptide repeats and reduced activity, revealing the molecular mechanisms contributing to pathogenesis...
March 23, 2018: Cell Chemical Biology
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