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Cell Chemical Biology

Daniel W Bak, Jinjun Gao, Chu Wang, Eranthie Weerapana
Mammalian selenocysteine (Sec)-containing proteins, selenoproteins, are important to (patho)physiological processes, including redox homeostasis. Sec residues have been recalcitrant to mass spectrometry-based chemoproteomic methods that enrich for reactive cysteine (Cys) residues with electrophilic chemical probes, despite confirmed reactivity of Sec with these electrophiles. Highly abundant Cys peptides likely suppress low-abundant Sec peptides. By exploiting the decreased pKa of Sec relative to Cys, we have developed a chemoproteomic platform that relies on low pH (pH 5...
June 12, 2018: Cell Chemical Biology
Mary Sabulski Feigman, Seonghoon Kim, Sean E Pidgeon, Yuming Yu, George Mogambi Ongwae, Dhilon S Patel, Steven Regen, Wonpil Im, Marcos M Pires
While traditional drug discovery continues to be an important platform for the search of new antibiotics, alternative approaches should also be pursued to complement these efforts. We herein designed a class of molecules that decorate bacterial cell surfaces with the goal of re-engaging components of the immune system toward Escherichia coli and Pseudomonas aeruginosa. More specifically, conjugates were assembled using polymyxin B (an antibiotic that inherently attaches to the surface of Gram-negative pathogens) and antigenic epitopes that recruit antibodies found in human serum...
June 12, 2018: Cell Chemical Biology
Torben Heise, Jeroen D Langereis, Emiel Rossing, Marien I de Jonge, Gosse J Adema, Christian Büll, Thomas J Boltje
Pathogens such as non-typeable Haemophilus influenzae (NTHi) evade the immune system by presenting host-derived sialic acids. NTHi cannot synthesize sialic acids and therefore needs to utilize sialic acids originating from host tissue. Here we report sialic acid-based probes to visualize and inhibit the transfer of host sialic acids to NTHi. Inhibition of sialic acid utilization by NTHi enhanced serum-mediated killing. Furthermore, in an in vitro model of the human respiratory tract, we demonstrate efficient inhibition of sialic acid transfer from primary human bronchial epithelial cells to NTHi using bioorthogonal chemistry...
June 9, 2018: Cell Chemical Biology
Melissanne de Wispelaere, Wenlong Lian, Supanee Potisopon, Pi-Chun Li, Jaebong Jang, Scott B Ficarro, Margaret J Clark, Xuling Zhu, Jenifer B Kaplan, Jared D Pitts, Thomas E Wales, Jinhua Wang, John R Engen, Jarrod A Marto, Nathanael S Gray, Priscilla L Yang
Viral envelope proteins are required for productive viral entry and initiation of infection. Although the humoral immune system provides ample evidence for targeting envelope proteins as an antiviral strategy, there are few pharmacological interventions that have this mode of action. In contrast to classical antiviral targets such as viral proteases and polymerases, viral envelope proteins as a class do not have a well-conserved active site that can be rationally targeted with small molecules. We previously identified compounds that inhibit dengue virus by binding to its envelope protein, E...
June 1, 2018: Cell Chemical Biology
Václav Beránek, Christopher D Reinkemeier, Michael S Zhang, Alexandria D Liang, Gene Kym, Jason W Chin
Protein phosphorylation regulates diverse processes in eukaryotic cells. Strategies for installing site-specific phosphorylation in target proteins in eukaryotic cells, through routes that are orthogonal to enzymatic post-translational modification, would provide a powerful route for defining the consequences of particular phosphorylations. Here we show that the SepRSv1.0 /tRNAv1.0 CUA pair (created from the Methanococcus maripaludis phosphoseryl-transfer RNA synthetase [MmSepRS]/Methanococcus janaschii [Mj]tRNAGCA Cys pair) is orthogonal in mammalian cells...
May 31, 2018: Cell Chemical Biology
Chin-Yuan Chang, Xiaohui Yan, Ivana Crnovcic, Thibault Annaval, Changsoo Chang, Boguslaw Nocek, Jeffrey D Rudolf, Dong Yang, Hindra, Gyorgy Babnigg, Andrzej Joachimiak, George N Phillips, Ben Shen
The enediynes, microbial natural products with extraordinary cytotoxicities, have been translated into clinical drugs. Two self-resistance mechanisms are known in the enediyne producers-apoproteins for the nine-membered enediynes and self-sacrifice proteins for the ten-membered enediyne calicheamicin. Here we show that: (1) tnmS1, tnmS2, and tnmS3 encode tiancimycin (TNM) resistance in its producer Streptomyces sp. CB03234, (2) tnmS1, tnmS2, and tnmS3 homologs are found in all anthraquinone-fused enediyne producers, (3) TnmS1, TnmS2, and TnmS3 share a similar β barrel-like structure, bind TNMs with nanomolar KD values, and confer resistance by sequestration, and (4) TnmS1, TnmS2, and TnmS3 homologs are widespread in nature, including in the human microbiome...
May 29, 2018: Cell Chemical Biology
Michael D Birnbaum, Leah Nemzow, Akhilesh Kumar, Feng Gong, Fangliang Zhang
Mutagenesis reporters are critical for quantifying genome stability. However, current methods rely on cell survival/death to report mutation, which takes weeks and prevents evaluation of acute or time-dependent changes. Existing methods also have other limitations, such as cell type restrictions. Using our discovery that mCherryFP fluorescence depends on residue Trp98, we replaced this codon with a stop codon to generate a mutation biosensor (termed CherryOFF), with a green fluorescence protein (GFP) as an internal control...
May 28, 2018: Cell Chemical Biology
Clifford M Csizmar, Jacob R Petersburg, Carston R Wagner
The ability to direct targeted intercellular interactions has the potential to enable and expand the use of cell-based therapies for regenerative medicine, tissue engineering, and immunotherapy. While genetic engineering approaches have proven effective, these techniques are not amenable to all cell types and often yield permanent modifications with potentially long-lasting adverse effects, restricting their application. To circumvent these limitations, there is intense interest in developing non-genetic methods to modify cell membranes with functional groups that will enable the recognition of target cells...
May 22, 2018: Cell Chemical Biology
Sterling R Payne, Daniel I Pau, Amanda L Whiting, Ye Joon Kim, Blaze M Pharoah, Christina Moi, Christopher N Boddy, Federico Bernal
In response to environmental and other stresses, the σ54 subunit of bacterial RNA polymerase (RNAP) controls expression of several genes that play a significant role in the virulence of both plant and animal pathogens. Recruitment of σ54 to RNAP initiates promoter-specific transcription via the double-stranded DNA denaturation mechanism of the cofactor. The RpoN box, a recognition helix found in the C-terminal region of σ54 , has been identified as the component necessary for major groove insertion at the -24 position of the promoter...
May 21, 2018: Cell Chemical Biology
Jun-Yu Xu, Ya Xu, Zhen Xu, Lin-Hui Zhai, Yang Ye, Yingming Zhao, Xiaohe Chu, Minjia Tan, Bang-Ce Ye
Coenzyme A (CoA) esters of short fatty acids (acyl-CoAs) function as key precursors for the biosynthesis of various natural products and the dominant donors for lysine acylation. Herein, we investigated the functional interplay between beneficial and adverse effects of acyl-CoA supplements on the production of acyl-CoA-derived natural products in microorganisms by using erythromycin-biosynthesized Saccharopolyspora erythraea as a model: accumulation of propionyl-CoA benefited erythromycin biosynthesis, but lysine propionylation inhibited the activities of important enzymes involved in biosynthetic pathways of erythromycin...
May 21, 2018: Cell Chemical Biology
Jessie Peh, Matthew W Boudreau, Hannah M Smith, Paul J Hergenrother
The discovery of mutant or fusion kinases that drive oncogenesis, and the subsequent approval of specific inhibitors for these enzymes, has been instrumental in the management of some cancers. However, acquired resistance remains a significant problem in the clinic, limiting the long-term effectiveness of most of these drugs. Here we demonstrate a general strategy to overcome this resistance through drug-induced MEK cleavage (via direct procaspase-3 activation) combined with targeted kinase inhibition. This combination effect is shown to be general across diverse tumor histologies (melanoma, lung cancer, and leukemia) and driver mutations (mutant BRAF or EGFR, fusion kinases EML4-ALK and BCR-ABL)...
May 18, 2018: Cell Chemical Biology
Peter Man-Un Ung, Rayees Rahman, Avner Schlessinger
Protein kinases are dynamic, adopting different conformational states that are critical for their catalytic activity. We assess a range of structural features derived from the conserved αC helix and DFG motif to define the conformational space of the catalytic domain of protein kinases. We then construct Kinformation, a random forest classifier, to annotate the conformation of 3,708 kinase structures in the PDB. Our classification scheme captures known active and inactive kinase conformations and defines an additional conformational state, thereby refining the current understanding of the kinase conformational space...
May 17, 2018: Cell Chemical Biology
Baoen Chen, Yang Sun, Jixiao Niu, Gopala K Jarugumilli, Xu Wu
Protein lipidation is an important co- or posttranslational modification in which lipid moieties are covalently attached to proteins. Lipidation markedly increases the hydrophobicity of proteins, resulting in changes to their conformation, stability, membrane association, localization, trafficking, and binding affinity to their co-factors. Various lipids and lipid metabolites serve as protein lipidation moieties. The intracellular concentrations of these lipids and their derivatives are tightly regulated by cellular metabolism...
May 16, 2018: Cell Chemical Biology
Benjamin Guy Trist, Dominic James Hare, Kay Lorraine Double
Shared molecular pathologies between distinct neurodegenerative disorders offer unique opportunities to identify common mechanisms of neuron death, and apply lessons learned from one disease to another. Neurotoxic superoxide dismutase 1 (SOD1) proteinopathy in SOD1-associated familial amyotrophic lateral sclerosis (fALS) is recapitulated in idiopathic Parkinson disease (PD), suggesting that these two phenotypically distinct disorders share an etiological pathway, and tractable therapeutic target(s). Despite 25 years of research, the molecular determinants underlying SOD1 misfolding and toxicity in fALS remain poorly understood...
May 16, 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
Sharrol T Bachas, Adrian R Ferré-D'Amaré
The large yybP-ykoY family of bacterial riboswitches is broadly distributed phylogenetically. Previously, these gene-regulatory RNAs were proposed to respond to Mn2+ . X-ray crystallography revealed a binuclear cation-binding pocket. This comprises one hexacoordinate site, with six oxygen ligands, which preorganizes the second, with five oxygen and one nitrogen ligands. The relatively soft nitrogen ligand was proposed to confer affinity for Mn2+ , but how this excludes other soft cations remained enigmatic...
May 4, 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
Lena Rakers, David Grill, Anna L L Matos, Stephanie Wulff, Da Wang, Jonas Börgel, Martin Körsgen, Heinrich F Arlinghaus, Hans-Joachim Galla, Volker Gerke, Frank Glorius
Cholesterol is an essential component of most biological membranes and serves important functions in controlling membrane integrity, organization, and signaling. However, probes to follow the dynamic distribution of cholesterol in live cells are scarce and so far show only limited applicability. Herein, we addressed this problem by synthesizing and characterizing a class of versatile and clickable cholesterol-based imidazolium salts. We show that these cholesterol analogs faithfully mimic the biophysical properties of natural cholesterol in phospholipid mono- and bilayers, and that they integrate into the plasma membrane of cultured and primary human cells...
May 1, 2018: Cell Chemical Biology
Amanda C Kohler, Blake A Simmons, Kenneth L Sale
In an age of ever-increasing biotechnological and industrial demand for new and specialized biocatalysts, rational protein engineering offers a direct approach to enzyme design and innovation. Heme peroxidases, as indispensable oxidative biocatalysts, provide a relatively mild alternative to the traditional harsh, and often toxic, chemical catalysts, and subsequently, have found widespread application throughout industry. However, the potential for these enzymes is far greater than their present use, as processes are currently restricted to the more stable, but less catalytically powerful, subset of peroxidases...
April 28, 2018: Cell Chemical Biology
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