Wednesday, March 22, 2017

Nature Chemical Biology Contents: April 2017, Volume 13 No 4 pp 339 - 450

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Nature Chemical Biology


April 2017 Volume 13, Issue 4

Research Highlights
News and Views
Brief Communications

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Simultaneous quantification of protein order and disorder   pp339 - 342
Pietro Sormanni, Damiano Piovesan, Gabriella T Heller, Massimiliano Bonomi, Predrag Kukic et al.
Nuclear magnetic resonance spectroscopy is transforming our views of proteins by revealing how their structures and dynamics are closely intertwined to underlie their functions and interactions. Compelling representations of proteins as statistical ensembles are uncovering the presence and biological relevance of conformationally heterogeneous states, thus gradually making it possible to go beyond the dichotomy between order and disorder through more quantitative descriptions that span the continuum between them.

Research Highlights


Development: Marking the transition | Bioconjugation: Methionine's time to shine | Drug discovery: Uncoupling coupled transport | Imaging: Luciferase matchmaker

News and Views


Fatty acid synthases: Re-engineering biofactories   pp344 - 345
Timm Maier
Systematically modifying biological assembly lines for the synthesis of novel products remains a challenge. Structural insights and computational modeling have now paved the way for efficient redesigns of giant fatty acid synthases.

See also: Brief Communication by Zhu et al. | Brief Communication by Gajewski et al.

Chromatin biology: Breaking into the PRC2 cage   pp345 - 346
Daniel Holoch and Raphael Margueron
New small-molecule inhibitors of the histone methyltransferase PRC2 interfere with the allosteric activation of enzymatic activity. These compounds are effective against PRC2-dependent tumors that are resistant to catalytic inhibitors and provide important new tools for altering chromatin regulation.

See also: Article by Qi et al. | Article by He et al.

Protein folding: Illuminating chaperone activity   pp346 - 347
Danny M Hatters
Pharmacological chaperones are small drugs that stabilize a protein's fold and are being developed to treat diseases arising from protein misfolding. A mathematical framework to model their activity in cells enables insight into their mechanism and capacity to rescue protein foldedness.

See also: Brief Communication by Hingorani et al.

Signaling: Spatial regulation of axonal cAMP   pp348 - 349
Pierre Vincent and Liliana R Castro
In early-stage developing neurons, the cAMP-PKA (protein kinase A) signaling pathway is strongly inhibited. This negative control is later removed, unleashing cAMP-PKA signaling, particularly in distal axonal parts, thus allowing for axonal growth.

See also: Article by Gorshkov et al.

Chemical Biology
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Versatile modes of cellular regulation via cyclic dinucleotides   pp350 - 359
Petya Violinova Krasteva and Holger Sondermann
A review of the roles of cyclic dinucleotides (CDNs) in signaling systems including transcription, ion transport, bacterial secretion and eukaryotic immune responses, highlighting the diverse binding modes of CDNs by target proteins and functional insights gained from structural studies.

Brief Communications


Expanding the product portfolio of fungal type I fatty acid synthases   pp360 - 362
Zhiwei Zhu, Yongjin J Zhou, Anastasia Krivoruchko, Martin Grininger, Zongbao K Zhao et al.

Integration of heterologous enzymes into the reaction chambers of fungal fatty acid synthases (FASs) demonstrates the capacity of these megaenzymes for engineered production of short- and medium-chain fatty acids and methyl ketones.

See also: Brief Communication by Gajewski et al. | News and Views by Maier

Engineering fatty acid synthases for directed polyketide production   pp363 - 365
Jan Gajewski, Floris Buelens, Sascha Serdjukow, Melanie Janszen, Nina Cortina et al.

In vitro and in silico analysis enables the rational design of fatty acid synthase (FAS)-mediated pathways for the compartmentalized production of desirable fatty acids and a polyketide lactone.

See also: Brief Communication by Zhu et al. | News and Views by Maier

Structure and specificity of a permissive bacterial C-prenyltransferase   pp366 - 368
Sherif I Elshahawi, Hongnan Cao, Khaled A Shaaban, Larissa V Ponomareva, Thangaiah Subramanian et al.

Discovery and characterization of an unusually permissive C-prenyltransferase provides a biocatalytic route for generating novel prenylated compounds, including daptomycin derivatives with increased potency.
Chemical compounds

Ligand-promoted protein folding by biased kinetic partitioning   pp369 - 371
Karan S Hingorani, Matthew C Metcalf, Derrick T Deming, Scott C Garman, Evan T Powers et al.

Pharmacological chaperones improve folding of destabilized Escherichia coli dihydrofolate reductase (DHFR) and human disease-linked α-galactosidase A (α-GAL) by biasing the kinetic partitioning between folding, aggregation, and degradation. Chaperoning spares DHFR from aggregation and α-GAL from degradation.

See also: News and Views by Hatters

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HTS-compatible FRET-based conformational sensors clarify membrane receptor activation   pp372 - 380
Pauline Scholler, David Moreno-Delgado, Nathalie Lecat-Guillet, Etienne Doumazane, Carine Monnier et al.

Optimizing the signal-to-noise ratio in time-resolved FRET through generation of agonist-responsive cell-surface receptor biosensors, including GABAB receptors and EGFR, which are useful for monitoring conformational changes associated with receptor activation.
Chemical compounds

An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of EED   pp381 - 388
Wei Qi, Kehao Zhao, Justin Gu, Ying Huang, Youzhen Wang et al.

H3K27me3 binding to the EED pocket of the Polycomb repressive complex 2 (PRC2) is required to activate PRC2. An allosteric small-molecule inhibitor of PRC2 was identified that binds to the EED pocket and blocks PRC2 methyltransferase activity in cells.
Chemical compounds
See also: Article by He et al. | News and Views by Holoch & Margueron

The EED protein-protein interaction inhibitor A-395 inactivates the PRC2 complex   pp389 - 395
Yupeng He, Sujatha Selvaraju, Michael L Curtin, Clarissa G Jakob, Haizhong Zhu et al.

A pyrrolidine-based small-molecule inhibitor competes with H3K27me3 for binding to EED leading to inactivation of PRC2 and global reduction in H3K27me3 levels.
Chemical compounds
See also: Article by Qi et al. | News and Views by Holoch & Margueron

In vitro reconstitution demonstrates the cell wall ligase activity of LCP proteins   pp396 - 401
Kaitlin Schaefer, Leigh M Matano, Yuan Qiao, Daniel Kahne and Suzanne Walker

Reconstitution experiments using substrates prepared by chemoenzymatic synthesis demonstrate that three LCP family proteins catalyze the ligation of wall teichoic acids to peptidoglycan in the biosynthesis of the Staphylococcus aureus cell wall.

A water-mediated allosteric network governs activation of Aurora kinase A   pp402 - 408
Soreen Cyphers, Emily F Ruff, Julie M Behr, John D Chodera and Nicholas M Levinson

Spectroscopic studies of allosteric activation of Aurora A kinase using a site-specific infrared probe combined with FRET analysis and molecular dynamics simulations reveals a water-mediated hydrogen bond network in the active site that regulates Aurora A activity.

A tight tunable range for Ni(II) sensing and buffering in cells   pp409 - 414
Andrew W Foster, Rafael Pernil, Carl J Patterson, Andrew J P Scott, Lars-Olof Palsson et al.

The Ni(ii) affinity of Ni(ii) sensor InrS is attuned to buffered Ni(ii) concentrations, explaining why these two parameters co-vary for different metals over many orders of magnitude.

Selective in vivo metabolic cell-labeling-mediated cancer targeting   pp415 - 424
Hua Wang, Ruibo Wang, Kaimin Cai, Hua He, Yang Liu et al.

Metabolic labeling of the cell surface with a caged azide sugar enabled cleavage-mediated activation by enzymes overexpressed in cancer cells, allowing enhanced targeted delivery of a doxorubicin conjugate through copper-free click chemistry.
Chemical compounds

AKAP-mediated feedback control of cAMP gradients in developing hippocampal neurons   pp425 - 431
Kirill Gorshkov, Sohum Mehta, Santosh Ramamurthy, Gabriele V Ronnett, Feng-Quan Zhou et al.

A gradient of cAMP in developing hippocampal neurons that is important for axon elongation is shaped by spatial differences in phosphodiesterase localization and is maintained by AKAP-anchored PKA, as revealed by using FRET-based biosensors.

See also: News and Views by Vincent & Castro

Evolution of a split RNA polymerase as a versatile biosensor platform   pp432 - 438
Jinyue Pu, Julia Zinkus-Boltz and Bryan C Dickinson

Design of a proximity-dependent split RNA polymerase system and its optimization by phage-assisted continuous evolution (PACE) enabled the development of a family of activity-dependent split RNA polymerase biosensors regulated by small molecules or light.

The GlcN6P cofactor plays multiple catalytic roles in the glmS ribozyme   pp439 - 445
Jamie L Bingaman, Sixue Zhang, David R Stevens, Neela H Yennawar, Sharon Hammes-Schiffer et al.

Experimental work and computational modeling together reveal a suite of catalytic roles of the GlcN6P cofactor in the glmS ribozyme, including activation of the nucleophile, electrostatic stabilization, and alignment of the active site.

An orthogonalized platform for genetic code expansion in both bacteria and eukaryotes   pp446 - 450
James S Italia, Partha Sarathi Addy, Chester J J Wrobel, Lisa A Crawford, Marc J Lajoie et al.

In Escherichia coli, replacement of the endogenous tryptophanyl-tRNA synthetase-tRNA pair with its counterpart from Saccharomyces cerevisiae liberates the bacterial counterpart for directed evolution to incorporate unnatural amino acids in both E. coli and eukaryotes.
Chemical compounds

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