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Nature Chemical Biology

Glen Liszczak, Katharine L Diehl, Geoffrey P Dann, Tom W Muir
Recent studies report serine ADP-ribosylation on nucleosomes during the DNA damage response. We unveil histone H3 serine 10 as the primary acceptor residue for chromatin ADP-ribosylation and find that specific histone acetylation marks block this activity. Our results provide a molecular explanation for the well-documented phenomenon of rapid deacetylation at DNA damage sites and support the combinatorial application of PARP and HDAC inhibitors for the treatment of PARP-dependent cancers.
July 16, 2018: Nature Chemical Biology
Ankit Gupta, Jing Xu, Shirley Lee, Steven T Tsai, Bo Zhou, Kohei Kurosawa, Michael S Werner, Akiko Koide, Alexander J Ruthenburg, Yali Dou, Shohei Koide
Rapidly determining the biological effect of perturbing a site within a potential drug target could guide drug discovery efforts, but it remains challenging. Here, we describe a facile target validation approach that exploits monobodies, small synthetic binding proteins that can be fully functionally expressed in cells. We developed a potent and selective monobody to WDR5, a core component of the mixed lineage leukemia (MLL) methyltransferase complex. The monobody bound to the MLL interaction site of WDR5, the same binding site for small-molecule inhibitors whose efficacy has been demonstrated in cells but not in animals...
July 16, 2018: Nature Chemical Biology
Andrew C McShan, Kannan Natarajan, Vlad K Kumirov, David Flores-Solis, Jiansheng Jiang, Mareike Badstübner, Jugmohit S Toor, Clive R Bagshaw, Evgenii L Kovrigin, David H Margulies, Nikolaos G Sgourakis
Chaperones TAPBPR and tapasin associate with class I major histocompatibility complexes (MHC-I) to promote optimization (editing) of peptide cargo. Here, we use solution NMR to investigate the mechanism of peptide exchange. We identify TAPBPR-induced conformational changes on conserved MHC-I molecular surfaces, consistent with our independently determined X-ray structure of the complex. Dynamics present in the empty MHC-I are stabilized by TAPBPR and become progressively dampened with increasing peptide occupancy...
July 9, 2018: Nature Chemical Biology
Youngnam N Jin, Peter J Schlueter, Nathalie Jurisch-Yaksi, Pui-Ying Lam, Shan Jin, Woong Y Hwang, Jing-Ruey Joanna Yeh, Masaaki Yoshigi, Shao-En Ong, Monica Schenone, Christina R Hartigan, Steven A Carr, Randall T Peterson
Primordial germ cells (PGCs) form during early embryogenesis with a supply of maternal mRNAs that contain shorter poly(A) tails. How translation of maternal mRNAs is regulated during PGC development remains elusive. Here we describe a small-molecule screen with zebrafish embryos that identified primordazine, a compound that selectively ablates PGCs. Primordazine's effect on PGCs arises from translation repression through primordazine-response elements in the 3' UTRs. Systematic dissection of primordazine's mechanism of action revealed that translation of mRNAs during early embryogenesis occurs by two distinct pathways, depending on the length of their poly(A) tails...
July 9, 2018: Nature Chemical Biology
Yuichiro Mishima
No abstract text is available yet for this article.
July 9, 2018: Nature Chemical Biology
Suzana Markolovic, Qinqin Zhuang, Sarah E Wilkins, Charlotte D Eaton, Martine I Abboud, Maximiliano J Katz, Helen E McNeil, Robert K Leśniak, Charlotte Hall, Weston B Struwe, Rebecca Konietzny, Simon Davis, Ming Yang, Wei Ge, Justin L P Benesch, Benedikt M Kessler, Peter J Ratcliffe, Matthew E Cockman, Roman Fischer, Pablo Wappner, Rasheduzzaman Chowdhury, Mathew L Coleman, Christopher J Schofield
In the version of this article initially published, authors Sarah E. Wilkins, Charlotte D. Eaton, Martine I. Abboud and Maximiliano J. Katz were incorrectly included in the equal contributions footnote in the affiliations list. Footnote number seven linking to the equal contributions statement should be present only for Suzana Markolovic and Qinqin Zhuang, and the statement should read "These authors contributed equally: Suzana Markolovic, Qinqin Zhuang." The error has been corrected in the HTML and PDF versions of the article...
June 27, 2018: Nature Chemical Biology
Hayley J Donnella, James T Webber, Rebecca S Levin, Roman Camarda, Olga Momcilovic, Nora Bayani, Khyati N Shah, James E Korkola, Kevan M Shokat, Andrei Goga, John D Gordan, Sourav Bandyopadhyay
Dysregulation of the PI3K-AKT-mTOR signaling network is a prominent feature of breast cancers. However, clinical responses to drugs targeting this pathway have been modest, possibly because of dynamic changes in cellular signaling that drive resistance and limit drug efficacy. Using a quantitative chemoproteomics approach, we mapped kinome dynamics in response to inhibitors of this pathway and identified signaling changes that correlate with drug sensitivity. Maintenance of AURKA after drug treatment was associated with resistance in breast cancer models...
June 25, 2018: Nature Chemical Biology
Jiasong Li, Wendell P Griffith, Ian Davis, Inchul Shin, Jiangyun Wang, Fahui Li, Yifan Wang, Daniel J Wherritt, Aimin Liu
Cysteine dioxygenase (CDO) plays an essential role in sulfur metabolism by regulating homeostatic levels of cysteine. Human CDO contains a post-translationally generated Cys93-Tyr157 cross-linked cofactor. Here, we investigated this Cys-Tyr cross-linking by incorporating unnatural tyrosines in place of Tyr157 via a genetic method. The catalytically active variants were obtained with a thioether bond between Cys93 and the halogen-substituted Tyr157, and we determined the crystal structures of both wild-type and engineered CDO variants in the purely uncross-linked form and with a mature cofactor...
June 25, 2018: Nature Chemical Biology
Helena Shomar, Sophie Gontier, Niels J F van den Broek, Héctor Tejeda Mora, Marek J Noga, Peter-Leon Hagedoorn, Gregory Bokinsky
Carbapenems, a family of β-lactam antibiotics, are among the most powerful bactericidal compounds in clinical use. However, as rational engineering of native carbapenem-producing microbes is not currently possible, the present carbapenem supply relies upon total chemical synthesis of artificial carbapenem derivatives. To enable access to the full diversity of natural carbapenems, we have engineered production of a simple carbapenem antibiotic within Escherichia coli. By increasing concentrations of precursor metabolites and identifying a reducing cofactor of a bottleneck enzyme, we improved productivity by 60-fold over the minimal pathway and surpassed reported titers obtained from carbapenem-producing Streptomyces species...
June 25, 2018: Nature Chemical Biology
Wentao Kong, David R Meldgin, James J Collins, Ting Lu
Designer microbial consortia are an emerging frontier in synthetic biology that enable versatile microbiome engineering. However, the utilization of such consortia is hindered by our limited capacity in rapidly creating ecosystems with desired dynamics. Here we present the development of synthetic communities through social interaction engineering that combines modular pathway reconfiguration with model creation. Specifically, we created six two-strain consortia, each possessing a unique mode of interaction, including commensalism, amensalism, neutralism, cooperation, competition and predation...
June 25, 2018: Nature Chemical Biology
Vinayak Palve, Brent M Kuenzi, Uwe Rix
No abstract text is available yet for this article.
June 25, 2018: Nature Chemical Biology
Thu-Thuy T Dang, Jakob Franke, Ines Soares Teto Carqueijeiro, Chloe Langley, Vincent Courdavault, Sarah E O'Connor
Cyclization reactions that create complex polycyclic scaffolds are hallmarks of alkaloid biosynthetic pathways. We present the discovery of three homologous cytochrome P450s from three monoterpene indole alkaloid-producing plants (Rauwolfia serpentina, Gelsemium sempervirens and Catharanthus roseus) that provide entry into two distinct alkaloid classes, the sarpagans and the β-carbolines. Our results highlight how a common enzymatic mechanism, guided by related but structurally distinct substrates, leads to either cyclization or aromatization...
June 25, 2018: Nature Chemical Biology
Camilla A K Lundgren, Dan Sjöstrand, Olivier Biner, Matthew Bennett, Axel Rudling, Ann-Louise Johansson, Peter Brzezinski, Jens Carlsson, Christoph von Ballmoos, Martin Högbom
Superoxide is a reactive oxygen species produced during aerobic metabolism in mitochondria and prokaryotes. It causes damage to lipids, proteins and DNA and is implicated in cancer, cardiovascular disease, neurodegenerative disorders and aging. As protection, cells express soluble superoxide dismutases, disproportionating superoxide to oxygen and hydrogen peroxide. Here, we describe a membrane-bound enzyme that directly oxidizes superoxide and funnels the sequestered electrons to ubiquinone in a diffusion-limited reaction...
June 18, 2018: Nature Chemical Biology
Carlo Cosimo Campa, Jean Piero Margaria, Abhishek Derle, Marco Del Giudice, Maria Chiara De Santis, Luca Gozzelino, Francesca Copperi, Carla Bosia, Emilio Hirsch
Directional transport of recycling cargo from early endosomes (EE) to the endocytic recycling compartment (ERC) relies on phosphatidylinositol 3-phosphate (PtdIns(3)P) hydrolysis and activation of the small GTPase Rab11. However, how these events are coordinated is yet unclear. By using a novel genetically-encoded FRET biosensor for Rab11, we report that generation of endosomal PtdIns(3)P by the clathrin-binding phosphoinositide 3-kinase class 2 alpha (PI3K-C2α) controls the activation of Rab11. Active Rab11, in turn, prompts the recruitment of the phosphatidylinositol 3-phosphatase myotubularin 1 (MTM1), eventually enabling the release of recycling cargo from the EE and its delivery toward the ERC...
June 18, 2018: Nature Chemical Biology
Radosław P Nowak, Stephen L DeAngelo, Dennis Buckley, Zhixiang He, Katherine A Donovan, Jian An, Nozhat Safaee, Mark P Jedrychowski, Charles M Ponthier, Mette Ishoey, Tinghu Zhang, Joseph D Mancias, Nathanael S Gray, James E Bradner, Eric S Fischer
Heterobifunctional small-molecule degraders that induce protein degradation through ligase-mediated ubiquitination have shown considerable promise as a new pharmacological modality. However, we currently lack a detailed understanding of the molecular basis for target recruitment and selectivity, which is critically required to enable rational design of degraders. Here we utilize a comprehensive characterization of the ligand-dependent CRBN-BRD4 interaction to demonstrate that binding between proteins that have not evolved to interact is plastic...
June 11, 2018: Nature Chemical Biology
Philip P Chamberlain
No abstract text is available yet for this article.
June 11, 2018: Nature Chemical Biology
Benoit Castrec, Cyril Dian, Sarah Ciccone, Coralie L Ebert, Willy V Bienvenut, Jean-Pierre Le Caer, Jean-Marc Steyaert, Carmela Giglione, Thierry Meinnel
An organism's entire protein modification repertoire has yet to be comprehensively mapped. N-myristoylation (MYR) is a crucial eukaryotic N-terminal protein modification. Here we mapped complete Homo sapiens and Arabidopsis thaliana myristoylomes. The crystal structures of human modifier NMT1 complexed with reactive and nonreactive target-mimicking peptide ligands revealed unexpected binding clefts and a modifier recognition pattern. This information allowed integrated mapping of myristoylomes using peptide macroarrays, dedicated prediction algorithms, and in vivo mass spectrometry...
June 11, 2018: Nature Chemical Biology
Jianchao Li, Ruichi Zhu, Keyu Chen, Hui Zheng, Hongyu Zhao, Chongzhen Yuan, Hong Zhang, Chao Wang, Mingjie Zhang
The mammalian Atg8 family proteins are central drivers of autophagy and contain six members, classified into the LC3 and GABARAP subfamilies. Due to their high sequence similarity and consequent functional overlaps, it is difficult to delineate specific functions of Atg8 proteins in autophagy. Here we discover a super-strong GABARAP-selective inhibitory peptide harbored in 270/480 kDa ankyrin-G and a super-potent pan-Atg8 inhibitory peptide from 440 kDa ankyrin-B. Structural studies elucidate the mechanism governing the Atg8 binding potency and selectivity of the peptides, reveal a general Atg8-binding sequence motif, and allow development of a more GABARAP-selective inhibitory peptide...
June 4, 2018: Nature Chemical Biology
Christian S Lentz, Jessica R Sheldon, Lisa A Crawford, Rachel Cooper, Megan Garland, Manuel R Amieva, Eranthie Weerapana, Eric P Skaar, Matthew Bogyo
Serine hydrolases play diverse roles in regulating host-pathogen interactions in a number of organisms, yet few have been characterized in the human pathogen Staphylococcus aureus. Here we describe a chemical proteomic screen that identified ten previously uncharacterized S. aureus serine hydrolases that mostly lack human homologs. We termed these enzymes fluorophosphonate-binding hydrolases (FphA-J). One hydrolase, FphB, can process short fatty acid esters, exhibits increased activity in response to host cell factors, is located predominantly on the bacterial cell surface in a subset of cells, and is concentrated in the division septum...
May 16, 2018: Nature Chemical Biology
Leah C Ray, Debasis Das, Sonya Entova, Vinita Lukose, Andrew J Lynch, Barbara Imperiali, Karen N Allen
Polyprenol phosphate phosphoglycosyl transferases (PGTs) catalyze the first membrane-committed step in assembly of essential glycoconjugates. Currently there is no structure-function information to describe how monotopic PGTs coordinate the reaction between membrane-embedded and soluble substrates. We describe the structure and mode of membrane association of PglC, a PGT from Campylobacter concisus. The structure reveals a unique architecture, provides mechanistic insight and identifies ligand-binding determinants for PglC and the monotopic PGT superfamily...
May 16, 2018: Nature Chemical Biology
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