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Nature Chemical Biology Contents: January 2017, Volume 13 No 1 pp 1 - 126

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Nature Chemical Biology


January 2017 Volume 13, Issue 1

Research Highlights
News and Views
Brief Communications

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Research Highlights


RNA structure: Widening the probe | Biocatalysis: Custom carbon cycling | Neurodegeneration: Untangling tau | Protein folding: Minimizing frustration

News and Views


Genetic engineering: Chemical control for CRISPR editing   pp2 - 3
Isaac B Hilton and Charles A Gersbach
New approaches allow tight control over Cas9 activity using chemical induction. These studies expand the ability to rapidly induce and suppress Cas9-mediated nuclease activity and conditionally modulate the multiplex regulation of endogenous gene expression.

See also: Brief Communication by Maji et al. | Article by Liu et al.

Ferroptosis: Oxidized PEs trigger death   pp4 - 5
Katharina D'Herde and Dmitri V Krysko
Ferroptosis is characterized by accumulation of lipid peroxidation products and lethal ROS, but the source and identity of lipid death signals that cause toxicity are poorly defined. New studies reveal that ACSL4 controls sensitivity to ferroptosis and that oxidized phosphatidylethanolamines are critical for ferroptosis execution.

See also: Article by Kagan et al. | Article by Doll et al.

Natural products: Mapping an amazing thicket   pp6 - 7
Mark E Horsman and Christopher N Boddy
The Global Natural Products Social Molecular Networking (GNPS) resource and the DEREPLICATOR algorithm provide new tools for analyzing mass spectral data and enabling natural products discovery.

See also: Article by Mohimani et al.

RAS signaling: Divide and conquer   pp7 - 8
Matthew Holderfield and Deborah K Morrison
The role of RAS dimerization in tumor biology is an emerging area of preclinical cancer research. Characterization of a RAS monobody indicates that dimer formation is required for RAS signaling, revealing the dimer interface as a potential drug target.

See also: Article by Spencer-Smith et al.

Chemical Biology
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Brief Communications


Multidimensional chemical control of CRISPR-Cas9   pp9 - 11
Basudeb Maji, Christopher L Moore, Bernd Zetsche, Sara E Volz, Feng Zhang et al.

Small-molecule control of transcriptional activation and genome editing was achieved by tethering inducible protein degron domains to an engineered CRISPR-Cas9 system.

See also: News and Views by Hilton & Gersbach

Genome-wide genetic screening with chemically mutagenized haploid embryonic stem cells   pp12 - 14
Josep V Forment, Mareike Herzog, Julia Coates, Tomasz Konopka, Bianca V Gapp et al.

A genetic screening approach using chemically mutagenized haploid mouse embryonic stem cells combined with next-generation sequencing identified recessive suppressor point mutations that elicit resistance to 6-thioguanine.

A multi-step peptidolytic cascade for amino acid recovery in chloroplasts   pp15 - 17
Pedro F Teixeira, Beata Kmiec, Rui M M Branca, Monika W Murcha, Anna Byzia et al.

Mass spectrometry analysis of stromal extracts reveal a peptidolytic cascade in the plant chloroplast consisting of oligopeptidases and aminopeptidases that mediates the complete degradation of signal peptides to free amino acids.

Identification of G-quadruplexes in long functional RNAs using 7-deazaguanine RNA   pp18 - 20
Carika Weldon, Isabelle Behm-Ansmant, Laurence H Hurley, Glenn A Burley, Christiane Branlant et al.

A strategy called footprinting of long 7-deazaguanine-substituted RNA (FOLDeR) enables the identification of RNA G quadruplexes in long RNA.



Structure of p300 in complex with acyl-CoA variants   pp21 - 29
Zuzanna Kaczmarska, Esther Ortega, Afsaneh Goudarzi, He Huang, Sunjoo Kim et al.

Structural and biochemical studies of the histone acetyltransferase p300 in complex with acyl-CoA substrates reveal a lysine binding channel that accommodates a particular chain length to mediate efficient histone modification.

Dereplication of peptidic natural products through database search of mass spectra   pp30 - 37
Hosein Mohimani, Alexey Gurevich, Alla Mikheenko, Neha Garg, Louis-Felix Nothias et al.

Aggregated mass spectral data by consortia such as the Global Natural Products Social (GNPS) molecular networking infrastructure enable natural product discovery. DEREPLICATOR, validated on peptidic natural products, is a computational tool to identify known metabolites in complex samples.

See also: News and Views by Horsman & Boddy

Profiling drugs for rheumatoid arthritis that inhibit synovial fibroblast activation   pp38 - 45
Douglas S Jones, Anne P Jenney, Jennifer L Swantek, John M Burke, Douglas A Lauffenburger et al.

A systems-level look at the activation of joint synovial fibroblasts in rheumatoid arthritis patients in response to different activators and therapeutic kinase inhibitors shows that multivariate inhibitor effects depend on the nature of the activator, not on the disease state per se.

DPP8 and DPP9 inhibition induces pro-caspase-1-dependent monocyte and macrophage pyroptosis   pp46 - 53
Marian C Okondo, Darren C Johnson, Ramya Sridharan, Eun Bin Go, Ashley J Chui et al.

Inhibitors of the post-proline-cleaving serine proteases DPP8 and DPP9 trigger a lytic form of programmed cell death called pyroptosis by activating pro-caspase-1 without autoproteolysis.

Non-classical transpeptidases yield insight into new antibacterials   pp54 - 61
Pankaj Kumar, Amit Kaushik, Evan P Lloyd, Shao-Gang Li, Rohini Mattoo et al.

Carbapenem β-lactam antibiotics target non-classical transpeptidases, the L,D-transpeptidases, which act in an alternative Mycobacterium tuberculosis peptidoglycan synthesis pathway, informing the design of evolved carbapenems with improved antibacterial activity.
Chemical compounds

Inhibition of RAS function through targeting an allosteric regulatory site   pp62 - 68
Russell Spencer-Smith, Akiko Koide, Yong Zhou, Raphael R Eguchi, Fern Sha et al.

A monobody was identified that binds to an allosteric lobe at the α4-β6-α5 interface to block H- and K-RAS signaling and transformation by disrupting RAS dimerization and nanoclustering.

See also: News and Views by Holderfield & Morrison

Elucidation of gibberellin biosynthesis in bacteria reveals convergent evolution   pp69 - 74
Ryan S Nett, Mariana Montanares, Ariana Marcassa, Xuan Lu, Raimund Nagel et al.

Characterization of five enzymes involved in gibberellin production in rhizobia completes the elucidation of its biosynthetic pathway and indicates that bacteria have independently evolved this pathway separate from the ones found in plants and fungi.
Chemical compounds

Tunable thermal bioswitches for in vivo control of microbial therapeutics   pp75 - 80
Dan I Piraner, Mohamad H Abedi, Brittany A Moser, Audrey Lee-Gosselin and Mikhail G Shapiro

Engineering of temperature-sensitive DNA repressors led to thermal bioswitches, allowing Escherichia coli to respond sharply to temperature at tunable set points and enabling application to host diagnostics and disease therapy.

Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis   pp81 - 90
Valerian E Kagan, Gaowei Mao, Feng Qu, Jose Pedro Friedmann Angeli, Sebastian Doll et al.

Arachidonyl and adrenoyl PE phospholipids generated by ACSL4, an acyl-CoA synthase, are doubly or triply oxidized by lipoxygenases and other iron-containing sources of oxidation to promote ferroptotic cell death.

See also: News and Views by D'Herde & Krysko

ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition   pp91 - 98
Sebastian Doll, Bettina Proneth, Yulia Y Tyurina, Elena Panzilius, Sho Kobayashi et al.

ACSL4 is critical for induction of ferroptosis, a programmed form of necrotic cell death, through the production of long polyunsaturated fatty acids that can be inhibited in an in vivo ferroptosis model with a small molecule ACSL4 inhibitor.

See also: News and Views by D'Herde & Krysko

The RNA helicase Mtr4p is a duplex-sensing translocase   pp99 - 104
Eric M Patrick, Sukanya Srinivasan, Eckhard Jankowsky and Matthew J Comstock

Single-molecule high-resolution optical trapping techniques elucidate the molecular mechanisms underlying the unwinding of RNA duplexes by the helicase Mtr4p, including how it restricts directional translocation to duplex regions.

Ubiquitin utilizes an acidic surface patch to alter chromatin structure   pp105 - 110
Galia T Debelouchina, Karola Gerecht and Tom W Muir

Hydrogen-deuterium (H/D) exchange combined with NMR spectroscopy analysis of nucleosomal arrays identified an acidic patch on ubiquitin that mediates chromatin decompaction and further supports that ubiquitin-ubiquitin interactions are needed for chromatin solubilization.

Full antagonism of the estrogen receptor without a prototypical ligand side chain   pp111 - 118
Sathish Srinivasan, Jerome C Nwachukwu, Nelson E Bruno, Venkatasubramanian Dharmarajan, Devrishi Goswami et al.

A sulfonamide series lacking the prototypical side chain behave as full antagonists or inverse agonists of estrogen receptor (ERα) signaling in a graded fashion dependent on coactivator recruitment and helix-11 positioning.
Chemical compounds

A computationally engineered RAS rheostat reveals RAS-ERK signaling dynamics   pp119 - 126
John C Rose, Po-Ssu Huang, Nathan D Camp, Jordan Ye, Andrew M Leidal et al.

Computational design enables the generation of a chimeric construct of the RAS exchange factor SOS that is specifically activated by a small molecule. The expression of this construct in different cell types reveals distinct phosphorylation kinetics.

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