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| 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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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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| 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
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Article
| Open AccessStructural and biochemical analysis of family 92 carbohydrate-binding modules uncovers multivalent binding to β-glucans
Carbohydrate binding modules (CBMs) are non-catalytic domains found within multi-modular carbohydrate-active enzymes like glycoside hydrolases. Here, the authors show the crystal structures of two CBM family 92 members, which use three different surface binding sites to bind to β-glucans.
- Meng-Shu Hao
- , Scott Mazurkewich
- & Lauren S. McKee
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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 AccessGENESIS CGDYN: large-scale coarse-grained MD simulation with dynamic load balancing for heterogeneous biomolecular systems
Here, the authors report the development of heterogeneous domain decomposition with load balancing for large biological molecular dynamics simulations using residue-level coarse-grained models.
- Jaewoon Jung
- , Cheng Tan
- & Yuji Sugita
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| Open AccessShining light on dinoflagellate photosystem I
Dinoflagellates are ecologically important and essential to corals and other cnidarians as phytosymbionts, but their photosystems had been underexplored. Recently, photosystem I (PSI) of dinoflagellate Symbiodinium sp. was structurally characterized using cryo-Electron Microscopy (cryo-EM). These analyses revealed a distinct organization of the PSI supercomplex, including two previously unidentified subunits, PsaT and PsaU, and shed light on interactions between light harvesting antenna proteins and the PSI core. These results have implications with respect to the evolution of dinoflagellates and their association with cnidarians.
- Senjie Lin
- , Shuaishuai Wu
- & Arthur R. Grossman
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Article
| Open AccessModulation of peroxisomal import by the PEX13 SH3 domain and a proximal FxxxF binding motif
Import of proteins into peroxisomes depends on PEX5, PEX13 and PEX14. Here the authors obtain crystal structures and NMR data to show the recognition of diaromatic peptide motifs on a noncanonical surface of the PEX13 SH3 domain, revealing a dynamic network which modulates peroxisomal matrix import.
- Stefan Gaussmann
- , Rebecca Peschel
- & Michael Sattler
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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 AccessExposing the molecular heterogeneity of glycosylated biotherapeutics
The molecular heterogeneity of glycosylated biotherapeutics often complicates analysis by intact mass spectrometry. Here, the authors propose a simplified procedure for characterization that employs proton transfer charge reduction. Integration with glycomic and glycopeptide datasets can further provide glycoform-level information.
- Luis F. Schachner
- , Christopher Mullen
- & Wendy Sandoval
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Article
| Open AccessInsights into the inhibition of protospacer integration via direct interaction between Cas2 and AcrVA5
Here, the authors characterize an anti-CRISPR protein that prevents protospacer integration by Cas1-Cas2, providing structural insights that may benefit CRISPR-Cas systems research.
- Mingfang Bi
- , Wenjing Su
- & Xiaobing Mo
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Article
| Open AccessEmerging variants develop total escape from potent monoclonal antibodies induced by BA.4/5 infection
Many emerging SARS-CoV-2 variants partially escape the humoral immune response. Here, Liu et al. characterize 28 antibodies from BA.4/5 breakthrough infections and find attrition of neutralization and complete loss of function for variants with Spike mutations at positions 455 and 456.
- Chang Liu
- , Raksha Das
- & Gavin R. Screaton
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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 AccessCryo-EM structures of adenosine receptor A3AR bound to selective agonists
Adenosine A3 receptor (A3AR) holds promise for treating inflammatory and cancer conditions. Here, Cai et al. present cryo-EM structures of A3AR bound to agonists CF101 and CF102, offering insights into its activation and ligand interaction, crucial for developing targeted therapies.
- Hongmin Cai
- , Shimeng Guo
- & H. Eric Xu
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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 AccessOne substrate many enzymes virtual screening uncovers missing genes of carnitine biosynthesis in human and mouse
With structural models now available on a proteome scale, Malatesta et al. show that structure-based screening can help identify proteins catalyzing orphan reactions in metabolic pathways, offering functional insights beyond sequence-based approaches.
- Marco Malatesta
- , Emanuele Fornasier
- & Riccardo Percudani
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Article
| Open AccessA hemoprotein with a zinc-mirror heme site ties heme availability to carbon metabolism in cyanobacteria
Heme is an abundant cofactor required by nearly all known organisms. Here, authors discover a cyanobacterial protein with a distinct Zn-mirror heme site, which may function to sense heme and regulate energy metabolism.
- Nicolas Grosjean
- , Estella F. Yee
- & Crysten E. Blaby-Haas