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Conformations of Bcs1L undergoing ATP hydrolysis suggest a concerted translocation mechanism for folded iron-sulfur protein substrate
How folded proteins are translocated across membranes is unknown for eukaryotes. Here, the authors propose a concerted translocation mechanism used by the AAA-ATPase Bcs1 to retro-translocate fully folded Rieske iron-sulfur protein across mitochondrial inner membrane.
- Jingyu Zhan
- , Allison Zeher
- & Di Xia
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Article
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Two noncompeting human neutralizing antibodies targeting MPXV B6 show protective effects against orthopoxvirus infections
There are limited therapeutics available for treatment of mpox. In this study, the authors identify two non-competing human neutralizing monoclonal antibodies with protective effects against orthopoxvirus infection in a mouse model and structurally resolve the targeted epitope within the MPXV B6 protein.
- Runchu Zhao
- , Lili Wu
- & Qihui Wang
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Article
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Universal paramyxovirus vaccine design by stabilizing regions involved in structural transformation of the fusion protein
There is a lack of vaccines for prevention of human respirovirus 3 (RV3) infection. Bakkers et al. report the design of a stabilized RV3 preF protein vaccine candidate that induces strong neutralizing antibodies and protective responses in small animal models.
- Johannes P. M. Langedijk
- , Freek Cox
- & Mark J. G. Bakkers
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Article
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Structural insights into the DNA topoisomerase II of the African swine fever virus
African swine fever virus is the sole mammalian-infecting virus encoding a type II topoisomerases (pP1192R). The authors present pP1192R structures in different states, illustrating the enzymatic mechanisms of viral type II topoisomerases.
- Jingyuan Cong
- , Yuhui Xin
- & Yutao Chen
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Structures of co-transcriptional RNA capping enzymes on paused transcription complex
5′-end capping of pre-mRNA is tightly coupled with the pausing stage of transcription. Here, the authors determine the cryo-EM structures of the paused elongation complex in complex with RNGTT and with both RNGTT and CMTR1.
- Yan Li
- , Qianmin Wang
- & Ze Li
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Cryo-EM structures of Thogoto virus polymerase reveal unique RNA transcription and replication mechanisms among orthomyxoviruses
In this study the authors present the Thogoto virus polymerase cryo-EM structures and reveal unique RNA synthesis mechanisms among orthomyxoviruses. RNA synthesis by Thogoto virus polymerase is shown to be weakly dependent on the host factors ANP32A/B/E in human cells in contrast to influenza viruses.
- Lu Xue
- , Tiancai Chang
- & Xiaoli Xiong
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Structure and distinct supramolecular organization of a PSII-ACPII dimer from a cryptophyte alga Chroomonas placoidea
The authors report structure of PSII-ACPII from a cryptophyte alga Chroomonas placoidea, providing insights into a distinct supramolecular organization and assembly of antennas in the supercomplex and possible excitation energy transfer pathways.
- Zhiyuan Mao
- , Xingyue Li
- & Guangye Han
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Proton-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
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Apo 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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Human 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
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Structure 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
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A potent Henipavirus cross-neutralizing antibody reveals a dynamic fusion-triggering pattern of the G-tetramer
There are no approved interventions for Hendra or Nipah viruses. Here, the authors isolate a G glycoprotein-specific antibody with cross-neutralizing and in vivo protective activities, and structurally resolve its binding pattern to the G protein.
- Pengfei Fan
- , Mengmeng Sun
- & Sandra Chiu
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Human CD4-binding site antibody elicited by polyvalent DNA prime-protein boost vaccine neutralizes cross-clade tier-2-HIV strains
Here the authors isolate monoclonal antibody HmAb64 from a healthy volunteer who received an experimental polyvalent DNA prime-protein boost HIV vaccine, and show that it’s specific for the CD4 binding site and neutralizes cross-subtype HIV isolates including several tier-2 viruses.
- Shixia Wang
- , Kun-Wei Chan
- & Shan Lu
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Mitoribosome 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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Structural 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
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Structures 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
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The 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
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Interplay 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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Structures 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
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Structure 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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Cryo-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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Microfibril-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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Structural 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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Structural 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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Multimodal 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
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Molecular 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
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Structural 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
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Structural 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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Impact 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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A 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
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Deciphering 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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Platform-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
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Structural 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
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Unraveling 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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Alternative 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
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Substrate 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
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Cyclodipeptide 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
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Structural 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
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Mechanism 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
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Structural 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
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Structural 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 Access
RNA 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
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The 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
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Mechanism 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
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Sm-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
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A 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
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Dynamic 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
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Structural 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
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A 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
Structural basis for human mitochondrial tRNA maturation