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News and Views

Targeted protein degradation: You can glue it too! pp452 - 453

Michal J Walczak, Georg Petzold & Nicolas H Thomä

doi:10.1038/nchembio.2355

Proteolysis-targeting chimera (PROTACs) are synthetic molecules that recruit neo-substrate proteins to a ubiquitin ligase for ubiquitination and subsequent degradation. Structural insight into the VHL–MZ1–BRD4 complex reveals how the rationally designed MZ1–PROTAC molecule mediates degradation of an unnatural protein substrate.

See also: Article by Gadd et al.


Microbiology: A new language for small talk pp453 - 454

Yi-Ming Shi & Helge B Bode

doi:10.1038/nchembio.2362

A new signal–receptor pair involved in regulating biofilm formation and virulence was detected in Vibrio cholerae. Both the signal and the transcription factor belong to common classes of natural products and receptor proteins, suggesting widespread importance of related systems in nature.

See also: Article by Papenfort et al.


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Review

The chemical basis for electrical signaling pp455 - 463

William A Catterall, Goragot Wisedchaisri & Ning Zheng

doi:10.1038/nchembio.2353

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A highlight of the knowledge derived in large part from structural work on physical motions and chemical interactions involved in voltage sensing, pore opening, ion conductance and selectivity, and voltage-dependent inactivation mechanisms of the voltage-gated channels NaV and CaV.


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Brief Communications

A fully automated flow-based approach for accelerated peptide synthesis pp464 - 466

Alexander J Mijalis, Dale A Thomas III, Mark D Simon, Andrea Adamo, Ryan Beaumont, Klavs F Jensen & Bradley L Pentelute

doi:10.1038/nchembio.2318

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An automated method for solid-phase polypeptide synthesis capitalizes on rapid amide bond formation to enable the production of multiple traditionally difficult-to-synthesize sequences with both high yield and high purity.


Decoding cyclase-dependent assembly of hapalindole and fischerindole alkaloids pp467 - 469

Shasha Li, Andrew N Lowell, Sean A Newmister, Fengan Yu, Robert M Williams & David H Sherman

doi:10.1038/nchembio.2327

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Characterization of a family of Stigonematales (Stig) cyclases that catalyze stereoselective intramolecular C–C bond formation reveals the enzymatic origins of the complex stereochemical patterns in hapalindole and fischerindole alkaloids.


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Articles

A new genome-mining tool redefines the lasso peptide biosynthetic landscape pp470 - 478

Jonathan I Tietz, Christopher J Schwalen, Parth S Patel, Tucker Maxson, Patricia M Blair, Hua-Chia Tai, Uzma I Zakai & Douglas A Mitchell

doi:10.1038/nchembio.2319

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RODEO, an algorithm developed for RiPP natural product discovery, was applied to map out the gene clusters that encode and tailor lasso peptides and led to the identification and characterization of several new lasso peptide topologies.


The Arabidopsis O-fucosyltransferase SPINDLY activates nuclear growth repressor DELLA pp479 - 485

Rodolfo Zentella, Ning Sui, Benjamin Barnhill, Wen-Ping Hsieh, Jianhong Hu, Jeffrey Shabanowitz, Michael Boyce, Neil E Olszewski, Pei Zhou, Donald F Hunt & Tai-ping Sun

doi:10.1038/nchembio.2320

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Mass spectrometry analysis combined with in vitro assays reveals that SPINDLY is an O-fucosyltransferase that modifies the growth repressor DELLA and consequently enhances its activity to regulate transcription of target genes.


Capzimin is a potent and specific inhibitor of proteasome isopeptidase Rpn11 pp486 - 493

Jing Li, Tanya Yakushi, Francesco Parlati, Andrew L Mackinnon, Christian Perez, Yuyong Ma, Kyle P Carter, Sharon Colayco, Gavin Magnuson, Brock Brown, Kevin Nguyen, Stefan Vasile, Eigo Suyama, Layton H Smith, Eduard Sergienko, Anthony B Pinkerton, Thomas D Y Chung, Amy E Palmer, Ian Pass, Sonja Hess, Seth M Cohen & Raymond J Deshaies

doi:10.1038/nchembio.2326

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Two screening approaches converge on capzimin, a first-in-class inhibitor of the Rpn11 protease component of the 19S proteasome. Capzimin stabilizes polyubiquitinated substrates, induces the unfolded protein response, and blocks proliferation of cancer cells.


L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH pp494 - 500

Andrew M Intlekofer, Bo Wang, Hui Liu, Hardik Shah, Carlos Carmona-Fontaine, Ariën S Rustenburg, Salah Salah, M R Gunner, John D Chodera, Justin R Cross & Craig B Thompson

doi:10.1038/nchembio.2307

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Acidification enhances lactate dehydrogenase– and malate dehydrogenase–mediated promiscuous production of L-2-hydroxyglutarate (L-2HG) from α-ketoglutarate and stabilizes HIF-1α levels.


Total RNA-seq to identify pharmacological effects on specific stages of mRNA synthesis pp501 - 507

Sarah A Boswell, Andrew Snavely, Heather M Landry, L Stirling Churchman, Jesse M Gray & Michael Springer

doi:10.1038/nchembio.2317

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The application of strand-specific total RNA sequencing combined with metagene analysis enables detection of small-molecule-mediated effects on transcription initiation, elongation or RNA processing, and reveals that isoginkgetin blocks transcriptional elongation.


The structure of a nucleolytic ribozyme that employs a catalytic metal ion pp508 - 513

Yijin Liu, Timothy J Wilson & David M J Lilley

doi:10.1038/nchembio.2333

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The structure of the TS (formerly twister sister) ribozyme reveals details about its catalytic mechanism of nucleolytic self-cleavage using a hydrated magnesium ion, and illustrates key differences between it and the related twister ribozyme.


Structural basis of PROTAC cooperative recognition for selective protein degradation pp514 - 521

Morgan S Gadd, Andrea Testa, Xavier Lucas, Kwok-Ho Chan, Wenzhang Chen, Douglas J Lamont, Michael Zengerle & Alessio Ciulli

doi:10.1038/nchembio.2329

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The description of the crystal structure of the Brd4 PROTAC compound MZ1 in complex with the human E3 ubiquitin ligase VHL and the Brd4 bromodomain shines new light onto how PROTACs work and enables design of degraders with increased selectivity for Brd4.

See also: News and Views by Walczak et al.


The Rrp4–exosome complex recruits and channels substrate RNA by a unique mechanism pp522 - 528

Milos A Cvetkovic, Jan Philip Wurm, Maxime J Audin, Stefan Schütz & Remco Sprangers

doi:10.1038/nchembio.2328

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A methyl-TROSY NMR approach provides a detailed model for how the archaeal exosome cap recruits multiple RNA substrates and channels them one by one into the catalytic barrel for degradation.


In silico design of novel probes for the atypical opioid receptor MRGPRX2 pp529 - 536

Katherine Lansu, Joel Karpiak, Jing Liu, Xi-Ping Huang, John D McCorvy, Wesley K Kroeze, Tao Che, Hiroshi Nagase, Frank I Carroll, Jian Jin, Brian K Shoichet & Bryan L Roth

doi:10.1038/nchembio.2334

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High-throughput screening identifies opioid compounds and prodynorphin-derived peptide agonists of the G-protein-coupled receptor MRGPRX2 and informs a homology model that is used for in silico screening to find a small-molecule probe that provokes degranulation in mast cells, which express this receptor.


Metagenomic discovery of polybrominated diphenyl ether biosynthesis by marine sponges pp537 - 543

Vinayak Agarwal, Jessica M Blanton, Sheila Podell, Arnaud Taton, Michelle A Schorn, Julia Busch, Zhenjian Lin, Eric W Schmidt, Paul R Jensen, Valerie J Paul, Jason S Biggs, James W Golden, Eric E Allen & Bradley S Moore

doi:10.1038/nchembio.2330

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Metagenomic analysis and functional characterization of biosynthetic genes uncovers the basis for widespread polybrominated diphenyl ether biosynthesis in cyanobacterial endosymbionts of marine Dysideidae sponges.


The direct role of selenocysteine in [NiFeSe] hydrogenase maturation and catalysis pp544 - 550

Marta C Marques, Cristina Tapia, Oscar Gutiérrez-Sanz, Ana Raquel Ramos, Kimberly L Keller, Judy D Wall, Antonio L De Lacey, Pedro M Matias & Inês A C Pereira

doi:10.1038/nchembio.2335

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Structural and functional characterization of a [NiFeSe] hydrogenase and its conversion to the [NiFe] type by mutagenesis indicate roles for the selenocysteine residue in metal incorporation, catalysis, and protection against oxidative deactivation.


A Vibrio cholerae autoinducer–receptor pair that controls biofilm formation pp551 - 557

Kai Papenfort, Justin E Silpe, Kelsey R Schramma, Jian-Ping Cong, Mohammad R Seyedsayamdost & Bonnie L Bassler

doi:10.1038/nchembio.2336

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A new autoinducer–receptor pair, 3,5-dimethylpyrazin-2-ol (DPO)–VqmA, acts in parallel to canonical Vibrio cholerae quorum-sensing pathways. Downstream of VqmA is the small RNA target VqmR, which, like DPO, represses genes required for biofilm formation and toxin production.

See also: News and Views by Shi & Bode


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