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Article
| Open AccessDynamics underlie the drug recognition mechanism by the efflux transporter EmrE
Here, the authors reveal the protonation of a single membrane embedded glutamate residue within the homodimer of the efflux transporter EmrE modulates the structure and dynamics in an allosteric manner using NMR spectroscopy.
- Jianping Li
- , Ampon Sae Her
- & Nathaniel J. Traaseth
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Article
| Open AccessNucleosomal DNA has topological memory
Here, the authors develop Topo-seq to measure the DNA topology (∆Lk) restrained by individual nucleosomes in vivo. They show that nucleosome DNA topology is imprinted by its native chromatin context and persists when the nucleosome is relocated.
- Joana Segura
- , Ofelia Díaz-Ingelmo
- & Joaquim Roca
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Article
| Open AccessControl of artificial membrane fusion in physiological ionic solutions beyond the limits of electroformation
Membrane fusion is crucial for fabricating artificial membranes. Here, the authors present an approach combining electric field with hydraulic pressure to physically control the fusion, enabling tuning of the shape and size of the 3D freestanding lipid bilayers in physiological solutions.
- Bong Kyu Kim
- , Dong-Hyun Kang
- & Tae Song Kim
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Article
| Open AccessRegiodivergent biosynthesis of bridged bicyclononanes
Hypericum plants contain complex compounds with promising medicinal properties. Here, the authors report a pair of enzymes catalyzing prenylation and regiodivergent cyclization. The forged scaffolds are characteristic of hyperforin analogs.
- Lukas Ernst
- , Hui Lyu
- & Benye Liu
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Article
| Open AccessHairpin protein partitioning from the ER to lipid droplets involves major structural rearrangements
Lipid droplet (LD) function relies on protein partitioning between the endoplasmic reticulum (ER) and LD. The authors show that UBXD8 adopts distinct conformations in both membranes and undergoes structural rearrangements during ER-to-LD partitioning.
- Ravi Dhiman
- , Rehani S. Perera
- & Bianca Schrul
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Article
| Open AccessProton-coupled transport mechanism of the efflux pump NorA
Efflux pumps confer antibiotic resistance by coupling proton import with drug export. In this work, the authors uncover the proton-coupled transport mechanism for the clinically relevant efflux pump NorA from the pathogenic bacterium S. aureus.
- Jianping Li
- , Yan Li
- & Nathaniel J. Traaseth
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Article
| Open AccessApo and Aβ46-bound γ-secretase structures provide insights into amyloid-β processing by the APH-1B isoform
Incomplete proteolysis of amyloid-β (Aβ) peptides by γ-secretases is linked to Alzheimer’s disease. Using cryo-EM and functional analyses, this study uncovers the γ-secretase – Aβ46 structure and unveils key interactions for efficient Aβ cleavage.
- Ivica Odorčić
- , Mohamed Belal Hamed
- & Rouslan G. Efremov
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Article
| Open AccessSpa2 remodels ADP-actin via molecular condensation under glucose starvation
Here the authors show that Spa2 orchestrates adaptive actin remodelling in budding yeast by dynamically binding ADP-actin and inducing phase separation on F-actin, a crucial response to energy starvation.
- Qianqian Ma
- , Wahyu Surya
- & Yansong Miao
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Article
| Open AccessHuman neutralizing antibodies target a conserved lateral patch on H7N9 hemagglutinin head
Here the authors isolate two human antibodies, H7.HK1 and H7.HK2, that achieve broad and potent neutralization against H7N9 influenza by targeting a distinct lateral patch on the hemagglutinin head, thus making them favorable to complement other antibodies for combination therapy.
- Manxue Jia
- , Hanjun Zhao
- & Xueling Wu
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Article
| Open AccessProteomic analysis of the urothelial cancer landscape
Urothelial cancer is a challenging disease and an emerging field for targeted therapies. Here, the authors optimize clinical proteomics to provide proteome-level data on tumor specificity and identify robust prognostic subtypes with predictive information for repurposed drug candidates.
- Franz F. Dressler
- , Falk Diedrichs
- & Ákos Végvári
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Article
| Open AccessRab30 facilitates lipid homeostasis during fasting
Despite the importance of Rab GTPases in maintaining the integrity of vesicle trafficking, their physiological roles are not well understood. Here, the authors define a role for Rab30 in supporting lipid homeostasis during fasting in the mouse.
- Danielle M. Smith
- , Brian Y. Liu
- & Michael J. Wolfgang
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Article
| Open AccessContractile injection systems facilitate sporogenic differentiation of Streptomyces davawensis through the action of a phage tapemeasure protein-related effector
Bacteria can use contractile injection systems, similar to viral tail structures, to deliver toxic proteins into other cells. Here, Nagakubo et al. identify a related system that modulates sporulation in multicellular Streptomyces bacteria.
- Toshiki Nagakubo
- , Tatsuya Nishiyama
- & Masanori Toyofuku
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Article
| Open AccessUltrafast energy quenching mechanism of LHCSR3-dependent photoprotection in Chlamydomonas
The Light Harvesting Complex Stress-Related Protein (LHCSR) can protect algae from severe photodamage via energy-dependent quenching (qE). Here, the authors find that a photoproduct of carotenoid S1 state is populated in qE and depopulated in 7.5 ps.
- Mengyuan Zheng
- , Xiaojie Pang
- & Lijin Tian
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Article
| Open AccessBiochemical-free enrichment or depletion of RNA classes in real-time during direct RNA sequencing with RISER
It is difficult to detect low abundance RNAs in sequencing experiments, and biochemical methods to enrich or deplete specific RNAs are time-consuming, costly and can damage RNA. Here, authors develop a biochemical-free technology to enrich or deplete RNA classes in real-time during direct RNA sequencing.
- Alexandra Sneddon
- , Agin Ravindran
- & Eduardo Eyras
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Article
| Open AccessImpact of secretin receptor homo-dimerization on natural ligand binding
GPCRs can form functionally important dimers. Here, authors study impact of dimerization of the secretin receptor on peptide ligand binding and show high receptor conformational dynamics that facilitate G protein recruitment and activation.
- Kaleeckal G. Harikumar
- , Sarah J. Piper
- & Laurence J. Miller
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Article
| Open AccessA rationally designed miniature of soluble methane monooxygenase enables rapid and high-yield methanol production in Escherichia coli
Soluble methane monooxygenase (sMMO) is a potentially value biocatalyst, but production of active recombinant sMMO is very challenging. Here the authors report the rational design and construction of a catalytically active miniature sMMO which enables high-yield production of methanol in E. coli.
- Yeonhwa Yu
- , Yongfan Shi
- & Jeewon Lee
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Article
| Open AccessAngle between DNA linker and nucleosome core particle regulates array compaction revealed by individual-particle cryo-electron tomography
Here, using cryo-ET, the 3D structures of individual nucleosome particles were characterized to observe changes under varying ionic strengths and in the presence of protein H1, revealing key regulatory roles in chromatin organization dynamics.
- Meng Zhang
- , César Díaz-Celis
- & Gang Ren
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Article
| Open AccessStructure and inhibition of the human lysosomal transporter Sialin
Sialin transports multiple substrates including sialic acid out of lysosomes, and neurotransmitters into synaptic vesicles. This study reports the cryo-EM structures of Sialin in multiple states revealing its transport and pH-sensing mechanisms.
- Philip Schmiege
- , Linda Donnelly
- & Xiaochun Li
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Article
| Open AccessIn-depth organic mass cytometry reveals differential contents of 3-hydroxybutanoic acid at the single-cell level
Comprehensive single-cell metabolic profiling is critical for revealing phenotypic heterogeneity and elucidating the molecular mechanisms underlying biological processes. Here, the authors establish a novel single-cell metabolomics platform for in-depth organic mass cytometry.
- Shaojie Qin
- , Yi Zhang
- & Yu Bai
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Article
| Open AccessThe patatin-like protein PlpD forms structurally dynamic homodimers in the Pseudomonas aeruginosa outer membrane
The Omp85 superfamily is a widely distributed class of outer membrane proteins found in Gram-negative bacteria, mitochondria and chloroplasts. Here the authors show that PlpD has a different structure and topology than other Omp85 proteins that have been studied.
- Sarah E. Hanson
- , Tyrone Dowdy
- & Harris D. Bernstein
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Article
| Open AccessSolutes unmask differences in clustering versus phase separation of FET proteins
Biomolecular condensates form via phase separation of multivalent macromolecules. Phase separation is governed by solubility whereas multivalence drives percolation, also known as gelation. The authors in this work identify the distinct energy and length scales that influence phase separation versus percolation.
- Mrityunjoy Kar
- , Laura T. Vogel
- & Rohit V. Pappu
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Article
| Open AccessCystine-knot peptide inhibitors of HTRA1 bind to a cryptic pocket within the active site region
Here the authors use phage display to develop cystine-knot peptides that inhibit the trimeric serine protease HTRA1. Structural and biochemical characterisation uncovered binding of the peptides to a cryptic pocket that locked the active site in a noncompetent state.
- Yanjie Li
- , Yuehua Wei
- & Daniel Kirchhofer
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Article
| Open AccessDual-mode harvest solar energy for photothermal Cu2-xSe biomineralization and seawater desalination by biotic-abiotic hybrid
Biotic-abiotic photosynthetic systems hold great promise to innovate solar-driven chemical transformation. Here, the authors construct a biotic-abiotic hybrid system composed of Shewanella oneidensis MR-1 and biogenic Se0 nanoparticles for photothermal Cu2-xSe biomineralization and then for seawater desalination.
- Sheng-Lan Gong
- , YangChao Tian
- & Li-Jiao Tian
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Article
| Open AccessIntegrating cryo-OrbiSIMS with computational modelling and metadynamics simulations enhances RNA structure prediction at atomic resolution
Conventional structural biology techniques are limited in deciphering complex RNA structures and dynamic interactions. Here the authors show an integrated approach that combines cryogenic OrbiSIMS (cryo-OrbiSIMS) with computational methods for modelling RNA structures at atomic resolution.
- Shannon Ward
- , Alex Childs
- & Aditi N. Borkar
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Article
| Open AccessThe SUN-family protein Sad1 mediates heterochromatin spatial organization through interaction with histone H2A-H2B
Here authors identify the interaction between the SUN-family protein Sad1 and histone H2A-H2B in S. pombe, and reveal the roles of the Sad1-histone interaction in the association of heterochromatin with the nuclear envelope and heterochromatin silencing.
- Wenqi Sun
- , Qianhua Dong
- & Yong Chen
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Article
| Open AccessReceptor-like cytoplasmic kinases of different subfamilies differentially regulate SOBIR1/BAK1-mediated immune responses in Nicotiana benthamiana
Cell-surface receptors form the front line of plant immunity. Here, the authors show that the RLP co-receptors SOBIR1 and BAK1 directly phosphorylate each other, leading to activation of the immune receptor complex in which RLCKs are differentially required for production of reactive oxygen species that play a role in resistance against Phytophthora palmivora.
- Wen R. H. Huang
- , Ciska Braam
- & Matthieu H. A. J. Joosten
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Article
| Open AccessCellular structure of dinosaur scales reveals retention of reptile-type skin during the evolutionary transition to feathers
The evolution of feathers is associated with the evolution of related skin microstructures. Here, the authors demonstrate that Psittacosaurus, a non-avian feathered dinosaur, retained scaled skin like its ancestors in body regions lacking feathers.
- Zixiao Yang
- , Baoyu Jiang
- & Maria E. McNamara
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Article
| Open AccessHeliorhodopsin-mediated light-modulation of ABC transporter
Here, authors classify genes flanking the Heliorhodopsin (HeR)-encoding genes and identify highly conserved residues for protein–protein interactions, revealing a function of HeR as regulatory rhodopsin for multidrug resistance.
- Shin-Gyu Cho
- , Ji-Hyun Kim
- & Kwang-Hwan Jung
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Article
| Open AccessEmergent ribozyme behaviors in oxychlorine brines indicate a unique niche for molecular evolution on Mars
Mars, an attractive candidate for potential presence of extraterrestrial life, contains oxychlorine species such as perchlorate at its surface. Here, the authors show perchlorate brines support folding and catalysis of functional RNAs, while inactivating representative protein enzymes, and that perchlorate enables new ribozyme functions, including ribozyme catalyzed chlorination of organic molecules.
- Tanner G. Hoog
- , Matthew R. Pawlak
- & Aaron E. Engelhart
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Article
| Open AccessElevated Na is a dynamic and reversible modulator of mitochondrial metabolism in the heart
Heart failure is characterised by a detrimental rise in the intracellular sodium concentration. Here the authors show that this reversibly reprogrammes energy metabolism in the heart making this a possible therapeutic target for the development of new drugs.
- Yu Jin Chung
- , Zoe Hoare
- & Michael J. Shattock
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Article
| Open AccessMitoribosome structure with cofactors and modifications reveals mechanism of ligand binding and interactions with L1 stalk
This study uses cryo-EM, biochemical, and computational approaches to shed light on the fundamental mechanisms underlying the human mitoribosome function, including ligand binding, modifications, Fe-S clusters, and aging-related polyamines.
- Vivek Singh
- , Yuzuru Itoh
- & Alexey Amunts
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Article
| Open AccessFatal COVID-19 pulmonary disease involves ferroptosis
Ferroptosis is a form of cell death that has been associated with different diseases. Here the authors describe an association of ferroptosis with COVID-19 pulmonary pathologies in both patient samples and hamster model and suggest that the dysregulation in iron and lipid metabolism could provide targets to reduce pathology.
- Baiyu Qiu
- , Fereshteh Zandkarimi
- & Brent R. Stockwell
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Article
| Open AccessPreserving ester-linked modifications reveals glutamate and aspartate mono-ADP-ribosylation by PARP1 and its reversal by PARG
Ester-linked modifications are common but difficult to detect. Here, the authors present methods based on ester preservation and a sensitive antibody to reveal DNA damage-induced mono-ADP-ribosylation on aspartate and glutamate. This signal, part of the first wave of PARP1 signaling, is removed by PARG.
- Edoardo José Longarini
- & Ivan Matić
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Article
| Open AccessBioinformatics leading to conveniently accessible, helix enforcing, bicyclic ASX motif mimics (BAMMs)
Researchers mimic protein interface helices by stapling peptide side chains, or replacing hydrogen bonds with covalent ones, and synthetic helical mimics are heavily biased towards stapling. Here the authors describe bioinformatic discovery of hydrophobic triangles at helix N-termini, and rigid, bicyclic synthetic mimics of them.
- Tianxiong Mi
- , Duyen Nguyen
- & Kevin Burgess
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Article
| Open AccessThe 8-17 DNAzyme can operate in a single active structure regardless of metal ion cofactor
Here, the authors use solution-state NMR to characterize the structure of 8–17 DNAzyme, revealing that all metal cofactors induce the same DNAzyme fold in contrast to previous findings.
- Julia Wieruszewska
- , Aleksandra Pawłowicz
- & Witold Andrałojć
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Article
| Open AccessExon-junction complex association with stalled ribosomes and slow translation-independent disassembly
Bensaude et al. use a split luciferase approach to show that exon-junction complex assembly and disassembly occur faster when they are translation-dependent than when they are translation-independent; and they uncover an association with ribosomes.
- Olivier Bensaude
- , Isabelle Barbosa
- & Hervé Le Hir
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Article
| Open AccessStructure of HIV-1 RRE stem-loop II identifies two conformational states of the high-affinity Rev binding site
HIV relies on the RRE RNA interaction with Rev protein for nuclear export of viral mRNAs. The structure of the high-affinity Rev binding site in RRE in two conformations suggests a mechanism for initial Rev binding and oligomerization onto RRE.
- Jerricho Tipo
- , Keerthi Gottipati
- & Kyung H. Choi
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Article
| Open AccessAccelerating reliable multiscale quantum refinement of protein–drug systems enabled by machine learning
Biomacromolecule structures are vital for drug design. Here, the authors integrate one or two machine learning potentials in an ONIOM-based quantum refinement method, achieving reliable drug structures at an QM level in proteins with high efficiency.
- Zeyin Yan
- , Dacong Wei
- & Lung Wa Chung
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Article
| Open AccessExtracellular modulation of TREK-2 activity with nanobodies provides insight into the mechanisms of K2P channel regulation
K2P channels are important regulators of cellular electrical activity. Here the authors show how nanobody fragments can be used to detect and modulate TREK2 K2P channel activity to provide insight into the mechanism of gating.
- Karin E. J. Rödström
- , Alexander Cloake
- & Stephen J. Tucker
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Article
| Open AccessThe EV71 2A protease occupies the central cleft of SETD3 and disrupts SETD3-actin interaction
Enteroviruses are responsible for several human diseases without treatment. This study describes the molecular interactions between SETD3, actin, and viral 2A in viral replication, providing a framework for the development of host-targeted therapies against enteroviruses.
- Xiaopan Gao
- , Bei Wang
- & Sheng Cui
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Article
| Open AccessMycobacterial biotin synthases require an auxiliary protein to convert dethiobiotin into biotin
Lipid biosynthesis in the pathogen M. tuberculosis depends on biotin for posttranslational modification of key enzymes. Here, Qu et al. identify an auxiliary protein that is required by M. tuberculosis to synthesize biotin.
- Di Qu
- , Peng Ge
- & Dirk Schnappinger
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Article
| Open AccessStructure, mechanism, and evolution of the last step in vitamin C biosynthesis
Photosynthetic organisms, fungi, and animals contain distinct pathways for vitamin C biosynthesis, but the final biosynthetic step consistently involves an oxidation reaction catalysed by the aldonolactone oxidoreductases. Here, the authors investigate the origin and evolution of the diversified activities and substrate preferences featured by these enzymes using different methods and find evidence that they share a common ancestor.
- Alessandro Boverio
- , Neelam Jamil
- & Andrea Mattevi
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Article
| Open AccessSequential glycosylations at the multibasic cleavage site of SARS-CoV-2 spike protein regulate viral activity
Here, the authors show that GalNAc-T3 and T7 regulate furin cleavage of the SARS-CoV-2 spike protein via O-glycosylation. This influences viral assembly and infection, highlighting glycosylation as a host defense mechanism.
- Shengjun Wang
- , Wei Ran
- & Yang Mao
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Article
| Open AccessSer/Leu-swapped cell-free translation system constructed with natural/in vitro transcribed-hybrid tRNA set
The use of orthogonal genetic code can help to prevent the escape of hazardous genes through horizontal gene transfer. Here, the authors develop a cell-free translation system with the Ser/Leu-swapped genetic code using a hybrid tRNA set and show its application in enhancing the production of superfolder GFP.
- Tomoshige Fujino
- , Ryogo Sonoda
- & Hiroshi Murakami
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Article
| Open AccessCryo-EM structures of the human Elongator complex at work
Here the authors determined several cryo-EM structures of the human Elongator complex, which modifies anticodons of tRNAs. The structural work is complemented by functional analyses to understand this clinically relevant cellular machine at the molecular level.
- Nour-el-Hana Abbassi
- , Marcin Jaciuk
- & Sebastian Glatt
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Article
| Open AccessInterplay between Mg2+ and Ca2+ at multiple sites of the ryanodine receptor
Skeletal ryanodine receptor controls calcium mobilization indispensable for muscle contraction. Here, authors combine cryo-EM and molecular dynamics to uncover the structural basis of the intricate regulation of this channel by calcium and magnesium.
- Ashok R. Nayak
- , Warin Rangubpit
- & Montserrat Samsó
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Article
| Open AccessIRE1α determines ferroptosis sensitivity through regulation of glutathione synthesis
The endoplasmic reticulum (ER) is a major site of lipid peroxidation during ferroptosis. Here authors show that the ER protein IRE1α determines ferroptosis induction via regulating glutathione synthesis independent of the unfolded protein response.
- Dadi Jiang
- , Youming Guo
- & Albert C. Koong
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Article
| Open AccessPost-translational modification-dependent oligomerization switch in regulation of global transcription and DNA damage repair during genotoxic stress
Here the authors show that the human transcription elongation factor AF9, part of Super Elongation Complex (SEC), undergoes oligomerization which can be reverted by post-translational modification in regulation of global transcription.
- Prathama Talukdar
- , Sujay Pal
- & Debabrata Biswas
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Article
| Open AccessEnzyme-assisted high throughput sequencing of an expanded genetic alphabet at single base resolution
The expansion of the genetic code with synthetic nucleotides has broadened our ability to evolve DNA as a functional material, but we lack analytical tools for the expanded alphabet. Here the authors demonstrate an enzyme-assisted method for the sequencing of six-letter DNA.
- Bang Wang
- , Kevin M. Bradley
- & Steven A. Benner
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