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| 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 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 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 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 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 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 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 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 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 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 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 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 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 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 AccessStructural insights into the transporting and catalyzing mechanism of DltB in LTA D-alanylation
Here, the authors structurally and functionally characterise DltB, a member of the Membrane-Bound O-AcylTransferase (MBOAT) superfamily responsible for D-alanine incorporation in the cell wall of gram-positive bacteria.
- Pingfeng Zhang
- & Zheng Liu
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Article
| Open AccessStructural basis for antiepileptic drugs and botulinum neurotoxin recognition of SV2A
SV2A is a receptor for botulinum neurotoxin (BoNT) and new generation antiepileptic drugs (AEDs). Here the authors report cryo-EM structures of SV2A in complex with BoNT receptor binding domain and AEDs highlighting the difference in the binding affinity between AEDs.
- Atsushi Yamagata
- , Kaori Ito
- & Mikako Shirouzu
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Article
| Open AccessRNA targeting and cleavage by the type III-Dv CRISPR effector complex
Here, Schwartz, Bravo, and Ahsan et al. show how multi-subunit fusion proteins are arranged around a crRNA in a type III CRISPR-Cas effector to cleave target RNA. Structures and molecular dynamics of this complex show three distinct active sites that can be used for programmable RNA cleavage.
- Evan A. Schwartz
- , Jack P. K. Bravo
- & David W. Taylor
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Article
| Open AccessThe DEAD-box ATPase Dbp10/DDX54 initiates peptidyl transferase center formation during 60S ribosome biogenesis
Cruz et al. describe the role of Dbp10/DDX54 in remodeling rRNA structure within the immature eukaryotic peptidyl transferase center of the ribosome, coupling energy-dependent catalysis to a post-catalytic role in factor exchange during 60S ribosomal subunit assembly.
- Victor E. Cruz
- , Christine S. Weirich
- & Jan P. Erzberger
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Article
| Open AccessMechanism and structural dynamics of sulfur transfer during de novo [2Fe-2S] cluster assembly on ISCU2
The biogenesis of iron-sulfur proteins in eukaryotes is initiated by the mitochondrial core ISC complex. Here, the authors provide structural, biochemical and spectroscopic data to characterize sulfur transfer intermediates in the core ISC complex.
- Vinzent Schulz
- , Ralf Steinhilper
- & Roland Lill
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Article
| Open AccessSm-like protein Rof inhibits transcription termination factor ρ by binding site obstruction and conformational insulation
Said et al. used cryoEM, biochemistry and bioinformatics to uncover how the Sm-like protein Rof regulates transcription termination. Rof binds termination factor ρ, inhibiting ρ ring closure and its association with RNA or transcription complexes.
- Nelly Said
- , Mark Finazzo
- & Markus C. Wahl
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Article
| Open AccessA widely conserved protein Rof inhibits transcription termination factor Rho and promotes Salmonella virulence program
Bacterial protein Rof (Rho-off) directly interacts with bacterial factor Rho and inhibits Rho-dependent transcription termination. Here, authors report cryo-EM structure of Rho-Rof antitermination complex and reveal their role in bacterial pathogenesis.
- Jing Zhang
- , Shuo Zhang
- & Chengyuan Wang
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Article
| Open AccessDynamic inter-domain transformations mediate the allosteric regulation of human 5, 10-methylenetetrahydrofolate reductase
Here the authors present the cryo-EM structure of active and inhibited human MTHFR, revealing a dynamic inhibitory mechanism dependent on dual SAM binding. The resulting closed conformation features an autoinhibitory element effectively blocking enzymatic activity.
- Linnea K. M. Blomgren
- , Melanie Huber
- & Thomas J. McCorvie
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Article
| Open AccessStructural basis for dimerization of a paramyxovirus polymerase complex
The structure and function of polymerase dimers of non-segmented, negative-strand RNA viruses are poorly understood. Here, this study presents the structural basis for dimerization of a paramyxovirus L–P polymerase and its role in genome replication.
- Jin Xie
- , Mohamed Ouizougun-Oubari
- & Shuai Chen
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Article
| Open AccessA subgroup of light-driven sodium pumps with an additional Schiff base counterion
Light-driven sodium-pumping rhodopsins are unique ion transporters. Here, authors present a characterization of such rhodopsins with a modified active center allowing for efficient sodium transport under various environmental conditions.
- E. Podoliak
- , G. H. U. Lamm
- & K. Kovalev
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Article
| Open AccessConcerted transformation of a hyper-paused transcription complex and its reinforcing protein
Here, authors use cryoEM, biochemistry and molecular dynamics simulations to delineate a functional cycle of RfaH, a universally conserved transcription factor that undergoes a fold-switch during recruitment to the transcribing RNA polymerase.
- Philipp K. Zuber
- , Nelly Said
- & Stefan H. Knauer
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Article
| Open AccessThe assembly platform FimD is required to obtain the most stable quaternary structure of type 1 pili
Type 1 pili are crucial cell surface bacterial virulence factors. Here, the authors show that FimD is required to assemble the most stable quaternary pilus structure by ensuring that the resulting protein polymer is free of structural defects.
- Dawid S. Zyla
- , Thomas Wiegand
- & Rudi Glockshuber
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Article
| Open AccessCryo-EM structure of the human Asc-1 transporter complex
The human Asc-1-4F2hc complex plays an important role in the neural development and stability. Here, authors determine the cryo-EM structures of Asc-1-4F2hc complex in three states, revealing its substrate recognition and transport mechanism.
- Yaning Li
- , Yingying Guo
- & Renhong Yan
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Article
| Open AccessStructure and mechanisms of transport of human Asc1/CD98hc amino acid transporter
Asc1/CD98hc is a key regulator of small neutral amino acid transport in the brain and adipose tissue. Here, authors report the structure of semi-occluded hAsc1/CD98hc and provide a model for Asc1 exchange and facilitated diffusion modes of transport.
- Josep Rullo-Tubau
- , Maria Martinez-Molledo
- & Oscar Llorca
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Article
| Open AccessCryo-EM structures of prokaryotic ligand-gated ion channel GLIC provide insights into gating in a lipid environment
Gloeobacter proton-gated ion channel (GLIC) is a convenient model of pentameric ligand-gated ion channels. Here, Bharambe & Li et al. report structures and simulations of GLIC with insights into the role of lipids in GLIC gating mechanism.
- Nikhil Bharambe
- , Zhuowen Li
- & Sandip Basak
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Article
| Open AccessCryo-EM structures of pannexin 1 and 3 reveal differences among pannexin isoforms
Pannexins are large pore channels involved in ion and ATP release. Here the authors use cryo-EM structures of Pannexins 1 and 3 to demonstrate the effects of distinct residue substitutions on channel structure and function.
- Nazia Hussain
- , Ashish Apotikar
- & Aravind Penmatsa
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Article
| Open AccessArchitecture and regulation of filamentous human cystathionine beta-synthase
Cystathionine beta-synthase is a conserved essential enzyme of one-carbon metabolism. Here, the authors show that the enzyme oligomerises to form filaments that undergo conformational and morphological changes in response to its activator S-adenosyl-L-methionine, the global methyl donor.
- Thomas J. McCorvie
- , Douglas Adamoski
- & Wyatt W. Yue
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Article
| Open AccessStructural basis for phage-mediated activation and repression of bacterial DSR2 anti-phage defense system
The bacterial DSR2 defense system counters phage invasion by depleting NAD+. Here, Zhang et al. reveal molecular mechanisms underlying phage-mediated activation and repression of DSR2, enhancing our understanding of the bacterial-phage arms race.
- Jun-Tao Zhang
- , Xiao-Yu Liu
- & Ning Jia
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Article
| Open AccessStructural bases of inhibitory mechanism of CaV1.2 channel inhibitors
CaV1.2 is crucial in cardiac, vascular and neuronal function, serving as a target for many drugs. Here, authors identify the binding site of herb-derived drug tetrandrine, and explore inhibitory mechanism of L/T-type selective DHP drug benidipine.
- Yiqing Wei
- , Zhuoya Yu
- & Yan Zhao
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Article
| Open AccessStructural basis of Acinetobacter type IV pili targeting by an RNA virus
Here, the authors structurally characterise the interaction between Acinetobacter phage AP205 and the type IV Acinetobacter pili using cryo-electron microscopy, uncovering the mechanistic determinants of this interaction.
- Ran Meng
- , Zhongliang Xing
- & Junjie Zhang
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Article
| Open AccessArchitecture and activation of human muscle phosphorylase kinase
High-resolution cryo-EM study of human muscle phosphorylase kinase reveals its complex structure and how calcium ions activate it, offering insights into glycogen metabolism and kinase regulation.
- Xiaoke Yang
- , Mingqi Zhu
- & Junyu Xiao
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Article
| Open AccessPhosphorylation and O-GlcNAcylation at the same α-synuclein site generate distinct fibril structures
Here, the authors use cryo-EM to show that phosphorylating or O-GlcNAcylating α-synuclein on serine 87 leads to the formation of two distinct fibril structures. Both structures display reduced neurotoxicity and propagation activity.
- Jinjian Hu
- , Wencheng Xia
- & Yan-Mei Li