Featured
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Article |
Engineered receptors for soluble cellular communication and disease sensing
- Dan I. Piraner
- , Mohamad H. Abedi
- & Kole T. Roybal
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Research Briefing |
Errors in cell division stopped by an atypical cyclin-dependent kinase
The enzyme cyclin-dependent kinase 1 (CDK1) and its partner cyclin B1 were thought to be sufficient to achieve error-free cell division. But now CDK5, an atypical cyclin-dependent kinase mostly known for its functions in non-dividing neurons, is shown to help to reduce errors in cell division.
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Article |
Clinical functional proteomics of intercellular signalling in pancreatic cancer
TMEPro profiles the glycosylated secreted and plasma membrane proteome of 100 human pancreatic tissue samples, defines cell type origins and identifies potential paracrine cross-talk mediated through tyrosine phosphorylation.
- Peiwu Huang
- , Weina Gao
- & Ruijun Tian
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Article |
Mutant-selective AKT inhibition through lysine targeting and neo-zinc chelation
A mutant-selective AKT inhibitor shows potential as a targeted therapy for breast cancer, enabling enhanced target engagement and avoiding the dose-limiting toxicity associated with pan-AKT inhibitors.
- Gregory B. Craven
- , Hang Chu
- & Jack Taunton
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Technology Feature |
Five protein-design questions that still challenge AI
Tools such as Rosetta and AlphaFold have redefined the protein-engineering landscape. But some problems remain out of reach — for now.
- Sara Reardon
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News & Views |
Engineered receptors show how humans tell countless odour molecules apart
How do odorant receptors in the human nose recognize a wide variety of scent molecules? The structures of engineered versions of these receptors finally provide much-needed answers to this fundamental question.
- Rafaella G. Naressi
- & Bettina Malnic
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Article |
Engineered odorant receptors illuminate the basis of odour discrimination
Use of the consensus protein design method facilitated the generation of stable engineered mammalian odorant receptors to gain insight into the molecular properties of odorant–receptor interactions.
- Claire A. de March
- , Ning Ma
- & Hiroaki Matsunami
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News & Views |
AI-designed DNA sequences regulate cell-type-specific gene expression
Researchers have used artificial-intelligence models to create regulatory DNA sequences that drive gene expression in specific cell types. Such synthetic sequences could be used to target gene therapies to particular cell populations.
- Andreas R. Pfenning
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News & Views |
Smart insulin switches itself off in response to low blood sugar
Scientists have engineered a modified insulin that reduces its activity at low glucose levels. This glucose-responsive insulin could prevent people with diabetes from experiencing dangerously low blood glucose.
- David B. Sacks
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News |
‘Smart’ insulin prevents diabetic highs — and deadly lows
In animals, the molecule automatically reduced blood-sugar levels without causing them to dip too much.
- Diana Kwon
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Article
| Open AccessGlucose-sensitive insulin with attenuation of hypoglycaemia
NNC2215 is an insulin conjugate that can reversibly adjust its bioactivity in response to a diabetes-relevant glucose range in vivo.
- Thomas Hoeg-Jensen
- , Thomas Kruse
- & Rita Slaaby
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Article |
Mosquito taste responses to human and floral cues guide biting and feeding
Taste neurons of the mosquito Aedes albopictus regulate biting, feeding and egg-laying behaviours by responding to taste cues in human sweat, nectar and egg-laying sites via excitation or inhibition.
- Lisa S. Baik
- , Gaëlle J. S. Talross
- & John R. Carlson
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Article |
Transferrin receptor targeting chimeras for membrane protein degradation
Transferrin receptor targeting chimeras have been developed that enable targeting of drug resistance in epidermal growth factor receptor-driven lung cancer and reversible control of human primary chimeric antigen receptor T cells, representing a promising new family of bifunctional antibodies for targeted cancer therapy.
- Dingpeng Zhang
- , Jhoely Duque-Jimenez
- & Xin Zhou
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Article |
Targeted protein relocalization via protein transport coupling
Targeted protein relocalization using shuttle proteins with potent ligands amenable to incorporation into targeted relocalization activating molecules could be used to regulate cellular physiology and correct disease states in neurodegenerative diseases, cancer and genetic disorders.
- Christine S. C. Ng
- , Aofei Liu
- & Steven M. Banik
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News & Views |
Small molecules help misplaced proteins hitchhike around cells
Many diseases arise from the misplacement of proteins in cells. A potential solution to this problem has been developed: small molecules that help displaced proteins catch a ride with other proteins to return to their proper location.
- Robert Yvon
- & Christina M. Woo
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Article |
Catalytic asymmetric synthesis of meta benzene isosteres
A palladium-catalysed reaction converts hydrocarbon-derived precursors to chiral boron-containing nortricyclanes, and the shape of these nortricyclanes makes them plausible isosteres for meta disubstituted aromatic rings.
- Mingkai Zhang
- , Matthew Chapman
- & James P. Morken
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News & Views |
How to design a protein that can be switched on and off
Proteins have been designed that assemble in different ways depending on whether an ‘effector’ molecule is present — a demonstration of allostery, the phenomenon that enables switch-like control of protein functions in nature.
- A. Joshua Wand
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Article
| Open AccessStructural basis for transthiolation intermediates in the ubiquitin pathway
Structural analyses of analogues of stable ubiquitin transthiolation intermediates with E1, E2 and E3 enzymes reveal a population of intermediate states that provide insights into the directional transfer of ubiquitin between E1, E2 and E3.
- Tomasz Kochańczyk
- , Zachary S. Hann
- & Christopher D. Lima
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Article |
Propofol rescues voltage-dependent gating of HCN1 channel epilepsy mutants
Propofol repairs malfunctioning mutant HCN1 channels associated with epilepsy, and its unusual mechanism of action on these ion channels can potentially be exploited to design precision drugs targeting HCN channelopathies.
- Elizabeth D. Kim
- , Xiaoan Wu
- & Crina M. Nimigean
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Review Article |
Sophisticated natural products as antibiotics
This Review examines the diverse strategies utilized by naturally occurring antibiotics and suggests how they have provided, and will in future provide, inspiration for the design of novel antibiotics.
- Kim Lewis
- , Richard E. Lee
- & Ingo Wohlgemuth
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Article |
Transport and inhibition mechanisms of the human noradrenaline transporter
Cryo-electron microscopy structures of the noradrenaline transporter (NET) reveal binding modes of adrenaline, coordination of sodium and chloride ion binding and the binding sites and mechanisms of inhibition by conotoxin, bupropion and ziprasidone.
- Tuo Hu
- , Zhuoya Yu
- & Yan Zhao
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News |
Serious errors plague DNA tool that’s a workhorse of biology
Researchers analysed thousands of laboratory-made plasmids and discovered that nearly half of them had defects, raising questions of experimental reproducibility.
- Katherine Bourzac
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Review Article |
Expanding chemistry through in vitro and in vivo biocatalysis
This Review considers developments in enzymes, biosynthetic pathways and cellular engineering that enable their use in catalysis for new chemistry and beyond.
- Elijah N. Kissman
- , Max B. Sosa
- & Michelle C. Y. Chang
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Article |
Inhibition of M. tuberculosis and human ATP synthase by BDQ and TBAJ-587
Cryogenic electron microscopy structures of Mycobacterium tuberculosis ATP synthase and human ATP synthase bound to the anti-tuberculosis drug bedaquiline or its analogue TBAJ-587 shed light on drug binding and could lead to new treatments for tuberculosis.
- Yuying Zhang
- , Yuezheng Lai
- & Hongri Gong
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Technology Feature |
No CRISPR: oddball ‘jumping gene’ enzyme edits genomes without breaking DNA
A programmable RNA that bridges a genetic donor and a target could herald a safer and more flexible approach to large-scale chromosome changes.
- Heidi Ledford
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Article |
Covalent targeted radioligands potentiate radionuclide therapy
Radiopharmaceuticals engineered with click chemistry to selectively bind to tumour-specific proteins can be used to successfully target tumour cells, boosting the pharmacokinetics of radionuclide therapy and improving tumour regression.
- Xi-Yang Cui
- , Zhu Li
- & Zhibo Liu
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Article |
Release of a ubiquitin brake activates OsCERK1-triggered immunity in rice
The ubiquitin E3 ligase OsCIE1 acts as a brake to inhibit OsCERK1 during homeostasis; this brake is released after chitin stimulation.
- Gang Wang
- , Xi Chen
- & Ertao Wang
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News & Views |
Vaccine-enhancing plant extract could be mass produced in yeast
The Chilean soapbark tree is the source of QS-21 — a valuable but hard-to-obtain vaccine additive. Yeast strains engineered to express all components of the QS-21 biosynthetic pathway provide an alternative route to this therapeutic.
- Ryan Nett
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Research Briefing |
Toad psychedelic points to biological target for antidepressants
A hallucinogenic compound secreted by toads has served as a springboard for research into the therapeutic benefits of psychedelics. The findings suggest that these compounds exert antidepressant effects in part by binding an under-appreciated target in the brain.
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Article |
Boron catalysis in a designer enzyme
A completely genetically encoded boronic-acid-containing designer enzyme was created and characterized using X-ray crystallography, high-resolution mass spectrometry and 11B NMR spectroscopy, allowing chemistry that is unknown in nature and currently not possible with small-molecule catalysts.
- Lars Longwitz
- , Reuben B. Leveson-Gower
- & Gerard Roelfes
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Article |
Structural pharmacology and therapeutic potential of 5-methoxytryptamines
Detailed analyses of the serotonin receptor 5-HT1A and the psychedelic 5-methoxy-N,N-dimethyltryptamine reveal the differences in receptor structural pharmacology that mediate signalling specificity, efficacy and potency, findings that may facilitate the development of new neuropsychiatric therapeutics.
- Audrey L. Warren
- , David Lankri
- & Daniel Wacker
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Research Briefing |
A chemical method for selective labelling of the key amino acid tryptophan
A broadly applicable method allows selective, rapid and efficient chemical modification of the side chain of tryptophan amino acids in proteins. This platform enables systematic, proteome-wide identification of tryptophan residues, which can form a bond (called cation–π interaction) with positively charged molecules. Such interactions are key in many biochemical processes, including protein-mediated phase separation.
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Article |
Chemoproteomic discovery of a covalent allosteric inhibitor of WRN helicase
VVD-133214, a clinical-stage, covalent allosteric inhibitor of the helicase WRN, was well tolerated in mice and led to robust tumour regression in multiple microsatellite-instability-high colorectal cancer cell lines and patient-derived xenograft models.
- Kristen A. Baltgalvis
- , Kelsey N. Lamb
- & Todd M. Kinsella
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Career Q&A |
The beauty of what science can do when urgently needed
Working amid New York City’s pandemic response inspired Nili Ostrov’s approach to expanding the list of organisms that can be used in synthetic biology and engineering.
- Katherine Bourzac
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Article |
Proteome-scale discovery of protein degradation and stabilization effectors
A synthetic proteome-scale strategy enables the identification of a diverse range of human proteins that can induce the degradation or stabilization of a target protein in a proximity-dependent way.
- Juline Poirson
- , Hanna Cho
- & Mikko Taipale
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Article |
Structural insights into vesicular monoamine storage and drug interactions
Monoamines and neurotoxicants share a binding pocket in VMAT1 featuring polar sites for specificity and a wrist-and-fist shape for versatility, and monoamine enrichment in storage vesicles arises from dominant import via favoured lumenal-open transition of VMAT1 and protonation-precluded binding during its cytoplasmic-open transition.
- Jin Ye
- , Huaping Chen
- & Weikai Li
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News & Views |
Mammalian cells repress random DNA that yeast transcribes
In experiments dubbed the Random Genome Project, researchers have integrated DNA strands with random sequences into yeast and mouse cells to find the default transcriptional state of their genomes.
- Sean R. Eddy
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Article |
Oxidative cyclization reagents reveal tryptophan cation–π interactions
Global profiling of hyper-reactive tryptophan sites across whole proteomes using tryptophan chemical ligation by cyclization (Trp-CLiC) reveals a systematic map of tryptophan residues that participate in cation–π interactions, including functional sites that can regulate protein-mediated phase-separation processes.
- Xiao Xie
- , Patrick J. Moon
- & Christopher J. Chang
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Article
| Open AccessDecoding chromatin states by proteomic profiling of nucleosome readers
A multidimensional proteomics analysis of the interactions between around 2,000 nuclear proteins and over 80 modified dinucleosomes representing promoter, enhancer and heterochromatin states provides insights into how chromatin states are decoded by chromatin readers.
- Saulius Lukauskas
- , Andrey Tvardovskiy
- & Till Bartke
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Article
| Open AccessTargeted protein degradation via intramolecular bivalent glues
Studies using genetic screening, biophysical characterization and structural reconstitution elucidate the mechanism of action and enable rational design of a new class of functional compounds that glue target proteins to E3 ligases via intramolecularly bridging two domains to enhance intrinsic protein–protein interactions and promote target ubiquitination and degradation.
- Oliver Hsia
- , Matthias Hinterndorfer
- & Alessio Ciulli
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News |
Glow way! Bioluminescent houseplant hits US market for first time
Engineered petunia emits a continuous green glow thanks to genes from a light-up mushroom.
- Katherine Bourzac
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Research Briefing |
Synthesizing and identifying potential biomarkers to explore uncharted biochemistry
Public repositories of metabolomics data are expanding rapidly and can be leveraged to uncover previously undescribed metabolites. Reverse metabolomics is a workflow in which thousands of small compounds are synthesized using combinatorial chemistry, and their molecular ‘fingerprints’ are then used to discover where they are localized in tissues and biological fluids and how they are associated with health and disease in humans.
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News |
How does chronic stress harm the gut? New clues emerge
A bacterium in the intestines of stressed mice interferes with cells that protect against pathogens.
- Max Kozlov
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Article
| Open AccessAdding α,α-disubstituted and β-linked monomers to the genetic code of an organism
tRNA display enables the direct selection of orthogonal aminoacyl-tRNA synthetases that acylate orthogonal tRNAs with non-canonical monomers, enabling in vivo synthesis of proteins that include these monomers and expanding the repertoire of the genetic code.
- Daniel L. Dunkelmann
- , Carlos Piedrafita
- & Jason W. Chin
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Article
| Open AccessA new antibiotic traps lipopolysaccharide in its intermembrane transporter
A mechanism of lipid transport inhibition has been identified for a class of peptide antibiotics effective against resistant Acinetobacter strains, which may have applications in the inhibition of other Gram-negative pathogens.
- Karanbir S. Pahil
- , Morgan S. A. Gilman
- & Daniel Kahne
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Article |
Discovery of a structural class of antibiotics with explainable deep learning
An explainable deep learning model using a chemical substructure-based approach for the exploration of chemical compound libraries identified structural classes of compounds with antibiotic activity and low toxicity.
- Felix Wong
- , Erica J. Zheng
- & James J. Collins
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Article |
A light-driven enzymatic enantioselective radical acylation
Enzyme-bound ketyl radicals derived from thiamine diphosphate are selectively generated through single-electron oxidation by a photoexcited organic dye and shown to lead to enantioselective radical acylation reactions.
- Yuanyuan Xu
- , Hongwei Chen
- & Xiaoqiang Huang
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Article
| Open AccessReverse metabolomics for the discovery of chemical structures from humans
A new discovery strategy, ‘reverse metabolomics’, facilitates high-throughput matching of mass spectrometry spectra in public untargeted metabolomics datasets, and a proof-of-concept experiment identified an association between microbial bile amidates and inflammatory bowel disease.
- Emily C. Gentry
- , Stephanie L. Collins
- & Pieter C. Dorrestein
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News |
Engineered yeast breaks new record: a genome with over 50% synthetic DNA
Highly edited strain survives and replicates despite containing 7.5 artificial chromosomes.
- Katherine Bourzac
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