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| Open AccessStructural mechanism of bacteriophage lambda tail’s interaction with the bacterial receptor
Here, Ge et al use cryo-electron microscopy to resolve the structure of the bacteriophage lambda tail in complex with its LamB receptor from Shigella sonnei and shed light on the conformational changes that the phage tail fiber undergoes in response to binding.
- Xiaofei Ge
- & Jiawei Wang
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Article
| Open AccessStructures of the mumps virus polymerase complex via cryo-electron microscopy
The viral polymerase complex is crucial for both genome replication and transcription in non-segmented negative-strand RNA viruses. Here, the authors link varying structures of polymerase complexes with their dual functions and propose a sliding model for them to advance along the RNA templates.
- Tianhao Li
- , Mingdong Liu
- & Qing-Tao Shen
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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 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 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 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 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 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 AccessStructures of H5N1 influenza polymerase with ANP32B reveal mechanisms of genome replication and host adaptation
The authors demonstrate how avian H5N1 influenza A virus polymerase interacts with human ANP32B to facilitate the replication of the viral genetic information in mammalian hosts, revealing insights into cross-species transmission.
- Ecco Staller
- , Loïc Carrique
- & Ervin Fodor
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Article
| Open AccessStructure and genome editing of type I-B CRISPR-Cas
Here the authors present two cryo-EM structures of the Synechocystis sp. PCC 6714 (Syn) type I-B Cascade, revealing the molecular mechanisms that underlie RNA-directed Cascade assembly, target DNA recognition and local conformational changes of the effector complex upon R-loop formation.
- Meiling Lu
- , Chenlin Yu
- & Yibei Xiao
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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 AccessChemical manipulation of an activation/inhibition switch in the nuclear receptor PXR
PXR is a receptor activated by diverse compounds that triggers detoxification pathways in the cell, and blocking this receptor may increase the effectiveness of certain drugs. Here, the authors present the structural basis of PXR inhibition.
- Efren Garcia-Maldonado
- , Andrew D. Huber
- & Taosheng Chen
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Article
| Open AccessStructural and dynamic insights into the activation of the μ-opioid receptor by an allosteric modulator
Here, the authors utilise NMR and cryo-EM to characterise the binding of an allosteric modulator to μ-opioid receptor (MOR), revealing modulator binding can potentiate receptor activation by altering the conformational dynamics in the core region of MOR.
- Shun Kaneko
- , Shunsuke Imai
- & Ichio Shimada
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Article
| Open AccessMicrofibril-associated glycoprotein 4 forms octamers that mediate interactions with elastogenic proteins and cells
Microfibrillar-associated protein 4 (MFAP4) is involved in fibrotic and cardiovascular diseases. Wozny et al. reveal structural aspects mediating MFAP4 octamer formation critical for its interaction with elastogenic proteins and cells.
- Michael R. Wozny
- , Valentin Nelea
- & Dieter P. Reinhardt
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Article
| Open AccessTargeting bacterial nickel transport with aspergillomarasmine A suppresses virulence-associated Ni-dependent enzymes
Aspergillomarasmine A (AMA) chelates metal ions such as Zn2+ and Ni2+, which are essential for the activity of enzymes that are important for virulence of several pathogens. Here, Sychantha et al. show that AMA inhibits bacterial Ni2+ uptake and Ni-dependent enzymes, and reduces bacterial virulence in an animal infection model.
- David Sychantha
- , Xuefei Chen
- & Gerard D. Wright
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Article
| Open AccessThe structural basis for 2′−5′/3′−5′-cGAMP synthesis by cGAS
Here, the authors provide structural and biochemical data describing the mechanism through which cGAS synthesizes 2′−5′/3′−5′-cGAMP.
- Shuai Wu
- , Sandra B. Gabelli
- & Jungsan Sohn
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Article
| Open AccessStructural basis of human NOX5 activation
NADPH oxidase 5 (NOX5) is activated by Ca2+ signaling, catalyzing superoxide production by transferring electrons from intracellular NADPH to extracellular oxygen. Here the authors uncover the molecular basis of NOX5 activation and electron transfer.
- Chenxi Cui
- , Meiqin Jiang
- & Ji Sun
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Article
| Open AccessStructural insights into drug transport by an aquaglyceroporin
Pentamidine and melarsoprol are drugs used to treat sleeping sickness caused by Trypanosoma brucei. Here, authors present cryo-EM structures of TbAQP2 with molecular dynamic simulations, revealing mechanisms shaping substrate specificity and drug permeation.
- Wanbiao Chen
- , Rongfeng Zou
- & Chongyuan Wang
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Article
| Open AccessHigh-confidence 3D template matching for cryo-electron tomography
Enabling visual proteomics with high-confidence 3D template matching (TM) in CryoET. 3D TM precisely localizes macromolecular complexes, individual subunits, and different functional states in situ, revealing molecular interactions within cells.
- Sergio Cruz-León
- , Tomáš Majtner
- & Gerhard Hummer
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Article
| Open AccessGenetic and functional diversity of β-N-acetylgalactosamine-targeting glycosidases expanded by deep-sea metagenome analysis
Four β-N-acetylgalactosaminidase gene families were identified via deep-sea metagenome analysis. The biochemical and structural characterization of the aforementioned enzymes revealed their functional diversity and monophyletic evolutionary history.
- Tomomi Sumida
- , Satoshi Hiraoka
- & Takuro Nunoura
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Article
| Open AccessMultimodal binding and inhibition of bacterial ribosomes by the antimicrobial peptides Api137 and Api88
Proline-rich antimicrobial peptides (PrAMPs) inhibit bacterial protein biosynthesis. Here, the authors show that the honey-bee derived PrAMPs Api137 and Api88 inhibit bacterial ribosomes through multiple mechanisms, promising for drug development.
- Simon M. Lauer
- , Maren Reepmeyer
- & Ralf Hoffmann
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Article
| Open AccessMolecular basis of bacterial DSR2 anti-phage defense and viral immune evasion
The defense-associated sirtuin 2 (DSR2) system protects bacteria from phages by depleting NAD+. Here, authors elucidate the molecular mechanisms underlying DSR2 assembly, activation, and inhibition, providing important insights into bacterial anti-phage defense.
- Jiafeng Huang
- , Keli Zhu
- & Ang Gao
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Article
| Open AccessAptameric hirudins as selective and reversible EXosite-ACTive site (EXACT) inhibitors
Inspired by the biologics of hematophagous organisms such as leeches, the authors in this work design and create inhibtors of thrombin and factor Xa by linking exosite-binding aptamers with small molecule active site inhibtors. They coin these inhibitors EXACT inhibitors.
- Haixiang Yu
- , Shekhar Kumar
- & Bruce A. Sullenger
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Article
| Open AccessContemporary HIV-1 consensus Env with AI-assisted redesigned hypervariable loops promote antibody binding
HIV-1 Env consensus sequences that reflect recent sequences for clades B, C, and CRF01_AE were redesigned using AI-assisted methods to shorten hypervariable loops and limit strain-specific targeting. The modified Envs show improved antibody binding.
- Hongjun Bai
- , Eric Lewitus
- & Morgane Rolland
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Article
| Open AccessIntramolecular autoinhibition regulates the selectivity of PRPF40A tandem WW domains for proline-rich motifs
The specific recognition of a proline-rich motif in the intrinsically disordered region of SF1 by the PRPF40A tandem WW domains is modulated by an intramolecular autoinhibition, suggesting a general mechanism to enhance WW binding selectivity.
- Santiago Martínez-Lumbreras
- , Lena K. Träger
- & Michael Sattler
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Article
| Open AccessIdentification and characterization of small molecule inhibitors of the LINE-1 retrotransposon endonuclease
The LINE-1 retrotransposon is a target for the development of therapies to treat age-associated disease. Here the AUs describes the characterization of small molecule inhibitors of the endonuclease domain of LINE-1.
- Alexandra M. D’Ordine
- , Gerwald Jogl
- & John M. Sedivy
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Article
| Open AccessStructural basis and synergism of ATP and Na+ activation in bacterial K+ uptake system KtrAB
KtrAB complex is essential in K+ uptake for bacteria. Here authors illustrate the synergism of ATP and Na+ in activating K+ uptake of KtrAB from Bacillus subtilis and its gating mechanism, which may also shed light on other Na+-activated K+ channels.
- Wesley Tien Chiang
- , Yao-Kai Chang
- & Nien-Jen Hu
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Article
| Open AccessMechanistic basis of the dynamic response of TWIK1 ionic selectivity to pH
Using computer simulations authors identify the dynamic molecular motions controlling the structural conformation of the TWIK1 ion channel, showing that its ability to transport sodium upon acidification result from the evolution of the classical potassium-selective pore.
- Franck C. Chatelain
- , Nicolas Gilbert
- & Olivier Bignucolo
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Article
| Open AccessImpact of distinct FG nucleoporin repeats on Nup98 self-association
Here, the authors demonstrate that mutations in the FG repeats of Nup98 significantly reduce its self-association capabilities and present a cryoEM structure exhibiting higher stability per residue then previously observed, suggesting spatial variations in self-association.
- Alain Ibáñez de Opakua
- , Christian F. Pantoja
- & Markus Zweckstetter
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Article
| Open AccessStructural basis for the intracellular regulation of ferritin degradation
Ferritin, the cellular iron storage complex, binds NCOA4 and is trafficked to the lysosome for degradation and iron release. Here, authors present the cryo-EM structure of the NCOA4-Ferritin complex with biophysical and cellular characterization.
- Fabian Hoelzgen
- , Thuy T. P. Nguyen
- & Gabriel A. Frank
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Article
| Open AccessSARS-CoV-2 Mpro responds to oxidation by forming disulfide and NOS/SONOS bonds
The main protease, a key enzyme of SARS-CoV-2, can protect itself from oxidative damage. Here, Reinke, Schubert, and colleagues used XFEL radiation to image the enzyme, revealing the disulfide and NOS/SONOS bonds that form in response to oxygen.
- Patrick Y. A. Reinke
- , Robin Schubert
- & Thomas J. Lane
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Article
| Open AccessDeciphering DED assembly mechanisms in FADD-procaspase-8-cFLIP complexes regulating apoptosis
Here the authors structurally and mechanistically characterize the assembly of FADD, procaspase-8, and cFLIP through their death-effector domains (DEDs), providing insights into the regulation of apoptotic and necroptotic signalling.
- Chao-Yu Yang
- , Chia-I Lien
- & Su-Chang Lin
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Article
| Open AccessA conserved N-terminal motif of CUL3 contributes to assembly and E3 ligase activity of CRL3KLHL22
The assembly integrity of dimeric CRL3 E3 ligases are important in various physiological and pathological processes. Here, the authors show that an evolutionarily conserved CUL3 N-terminal motif contributes to both the assembly and activity of dimeric CRL3 E3 ligases.
- Weize Wang
- , Ling Liang
- & Yuxin Yin
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Article
| Open AccessA Toxoplasma gondii O-glycosyltransferase that modulates bradyzoite cyst wall rigidity is distinct from host homologues
A Toxoplasma gondii mucin-type O-glycosyltransferase uses a unique catalytic mechanism to modify bradyzoite cyst wall proteins. A second metal coupled to substrate binding is required for catalysis, while an active site glutamate suggests a double-displacement mechanism.
- Pranav Kumar
- , Tadakimi Tomita
- & Nadine L. Samara
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Article
| Open AccessActive site remodeling in tumor-relevant IDH1 mutants drives distinct kinetic features and potential resistance mechanisms
Here the authors show mutants of isocitrate dehydrogenase 1 (IDH1), an enzyme implicated in various cancers, have distinct catalytic and structural features that drive their ability to generate an oncometabolite.
- Matthew Mealka
- , Nicole A. Sierra
- & Christal D. Sohl
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| Open AccessPlatform-directed allostery and quaternary structure dynamics of SAMHD1 catalysis
SAMHD1 is a regulator of dNTP homeostasis and an HIV restriction factor. The authors use time-resolved cryo-EM to visualise dynamic conformational changes that drive the catalytic cycle and allosteric regulation of this multi-subunit enzyme.
- Oliver J. Acton
- , Devon Sheppard
- & Ian A. Taylor
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Article
| Open AccessHPK1 citron homology domain regulates phosphorylation of SLP76 and modulates kinase domain interaction dynamics
In this work, the authors unveil a mechanism where the Citron homology domain regulates HPK1’s kinase domain, shedding light on the relationship between HPK1’s structure and function. This enhances our understanding of HPK1, an intracellular target for cancer immunotherapy and provides a direction for immuno-oncology drug discovery.
- Avantika S. Chitre
- , Ping Wu
- & Weiru Wang
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Article
| Open AccessThe complete assembly of human LAT1-4F2hc complex provides insights into its regulation, function and localisation
The amino acid transporter complex LAT1-4F2hc is considered a major drug target for many cancers. Here, the authors apply native mass spectrometry-based approaches to decode a complete LAT1-4F2hc assembly. To do this, they connect post-translational modification and endogenous phospholipid binding to super-dimerization, function and localisation of LAT1-4F2hc.
- Di Wu
- , Renhong Yan
- & Carol V. Robinson
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Article
| Open AccessStructural mechanism of voltage-gated sodium channel slow inactivation
Inactivation is an intrinsic property of NaV channel, but the mechanism for slow inactivation is not fully understood. Here, authors show a NaVEh structure in a potential slow-inactivated state, elucidating structural basis for slow inactivation.
- Huiwen Chen
- , Zhanyi Xia
- & Daohua Jiang
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Article
| Open AccessUnraveling the mechanisms of PAMless DNA interrogation by SpRY-Cas9
CRISPR-Cas9 is a powerful tool, but the strict requirement for an “NGG” protospacer-adjacent motif (PAM) sequence limits the number of editable genes. Here the authors combine enzyme kinetics, cryo-EM, and single-molecule imaging to determine how SpRY interrogates DNA and recognises target sites for cleavage.
- Grace N. Hibshman
- , Jack P. K. Bravo
- & David W. Taylor
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Article
| Open AccessAlternative splicing controls teneurin-3 compact dimer formation for neuronal recognition
This study reveals how two splice inserts alter the conformation and dimeric arrangement of the teneurin-3 extracellular region. These insights elucidate the role of teneurin isoforms in neuronal recognition and circuit wiring.
- Christos Gogou
- , J. Wouter Beugelink
- & Dimphna H. Meijer
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Article
| Open AccessSubstrate binding plasticity revealed by Cryo-EM structures of SLC26A2
SLC26A2 transports crucial ions and mutations in it cause diverse diseases. Here, authors present cryo-EM structures of SLC26A2 with substrates, revealing details of its homodimer assembly, dynamic substrate binding, and effects of mutations.
- Wenxin Hu
- , Alex Song
- & Hongjin Zheng
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Article
| Open AccessCyclodipeptide oxidase is an enzyme filament
Many cyclic dipeptide natural products can be modified by cyclodipeptide oxidase enzymes. Here, the authors report the structural characterization of the cyclodipeptide oxidase AlbAB and show that it assembles into heterooligomeric enzyme filaments.
- Michael P. Andreas
- & Tobias W. Giessen
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Article
| Open AccessTargeted small molecule inhibitors blocking the cytolytic effects of pneumolysin and homologous toxins
The pore-forming toxin pneumolysin is responsible for the high mortality seen in pneumococcal infections unresponsive to antibiotics. In this work, authors report a small molecule inhibitor targeting pneumolysin and related ones as an anti-virulence strategy protecting human cells during infection.
- Umer Bin Abdul Aziz
- , Ali Saoud
- & Jörg Rademann
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Article
| Open AccessStructural insights into the functional mechanism of the ubiquitin ligase E6AP
The human papillomavirus (HPV) E6 oncoprotein hijacks the ligase activity of the host E6AP to ubiquitinate the tumor suppressor p53. Here, the authors show how the presence of the HPV E6 oncoprotein transforms the inactive E6AP monomer into an active dimer, providing a structural understanding of the physiological and pathophysiological mechanisms of E6AP function.
- Zhen Wang
- , Fengying Fan
- & Xuekui Yu
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Article
| Open AccessMechanism of Ψ-Pro/C-degron recognition by the CRL2FEM1B ubiquitin ligase
A key question in the ubiquitin-proteasome system is how E3 ligases select their substrates. Here, the authors reveal that CRL2FEM1B E3 ligase functions as a dimer and employs a bipartite mode of substrate recognition, requiring a C-terminal proline and an upstream aromatic residue in the target.
- Xinyan Chen
- , Anat Raiff
- & Chao Xu
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Article
| Open AccessGroup 3 medulloblastoma transcriptional networks collapse under domain specific EP300/CBP inhibition
The differential effects of targeting individual domains of multidomain enzymatic proteins are generally poorly understood. Here, the authors demonstrate lineage-specific sensitivities to domain-specific inhibition of EP300/CBP proteins across cancer and link these effects in group 3 medulloblastoma to control of a transcriptional dependency network.
- Noha A. M. Shendy
- , Melissa Bikowitz
- & Adam D. Durbin
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Article
| Open AccessNMR characterization of RNA binding property of the DEAD-box RNA helicase DDX3X and its implications for helicase activity
DDX3X is a member of the RNA helicase family, which remodels RNA structures. Using solution NMR, here the authors show that DDX3X preferentially binds to single-stranded RNA, which underlies its unwinding activity toward various structured RNA substrates.
- Yuki Toyama
- & Ichio Shimada