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| Open AccessDiverging co-translational protein complex assembly pathways are governed by interface energy distribution
Protein complex assembly can occur co-translationally. Here, the authors uncover diverging assembly pathways and hotspot disruptions in N-terminal acetyltransferases, enzymes implicated in neurodegenerative diseases. Their model predicts co-translational assembly based on interface energy distribution.
- Johannes Venezian
- , Hagit Bar-Yosef
- & Ayala Shiber
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Article
| Open AccessBidirectional ATP-driven transport of cobalamin by the mycobacterial ABC transporter BacA
ABC transporters are generally considered to be unidirectional. Here, the authors develop a fluorescence-based transport assay and show that the mycobacterial ABC transporter BacA instead acts as a bidirectional transporter for cobalamin.
- Mark Nijland
- , Solène N. Lefebvre
- & Dirk J. Slotboom
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Article
| Open AccessStructural basis for peroxidase encapsulation inside the encapsulin from the Gram-negative pathogen Klebsiella pneumoniae
Peroxidase encapsulins are self-assembling protein compartments involved in oxidative stress response found in many pathogens. Here, the authors characterize the structural basis of peroxidase encapsulation inside the Klebsiella pneumoniae encapsulin.
- Jesse A. Jones
- , Michael P. Andreas
- & Tobias W. Giessen
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Article
| Open AccessStructure of antiviral drug bulevirtide bound to hepatitis B and D virus receptor protein NTCP
Hepatitis B and D viruses require docking to the NTCP receptor protein for cell entry, an interaction that can be blocked by the drug bulevirtide. Here the authors use cryo-EM to reveal the structural basis of bulevirtide activity.
- Hongtao Liu
- , Dariusz Zakrzewicz
- & Kaspar P. Locher
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Article
| Open AccessStructural basis of ligand recognition and design of antihistamines targeting histamine H4 receptor
The histamine H4 receptor (H4R) plays key roles in immune cell function. Here, the authors report structures of H4R-Gi complex with various ligands bound, revealing distinct ligand binding modes and a basis for rational design of novel antihistamines targeting H4R.
- Ruixue Xia
- , Shuang Shi
- & Yuanzheng He
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Article
| Open AccessDissecting the mechanism of atlastin-mediated homotypic membrane fusion at the single-molecule level
The detailed process of membrane fusion mediated by dynamin-like GTPase atlastin (ATL) remains unclear. Here, authors reveal the conformational dynamics of ATL coupled with GTP hydrolysis cycle at the single molecule level.
- Lijun Shi
- , Chenguang Yang
- & Xin Bian
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Article
| Open AccessDrug-resistant EGFR mutations promote lung cancer by stabilizing interfaces in ligand-free kinase-active EGFR oligomers
The Epidermal Growth Factor Receptor (EGFR) is frequently found to be mutated in non-small cell lung cancer. Here, the authors show that EGFR lung cancer mutations promote the assembly of kinase-active dimers within ligand-free EGFR oligomers. These dimers bind ligand with high affinity and promote tumor growth.
- R. Sumanth Iyer
- , Sarah R. Needham
- & Marisa L. Martin-Fernandez
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Article
| Open AccessVCF1 is a p97/VCP cofactor promoting recognition of ubiquitylated p97-UFD1-NPL4 substrates
p97/VCP, a nexus of the ubiquitin system, recognizes and unfolds ubiquitylated substrates via multiple cofactors. Here, the authors identify VCF1, a nuclear cofactor promoting p97 recruitment to, and proteasomal degradation of, ubiquitylated targets.
- Ann Schirin Mirsanaye
- , Saskia Hoffmann
- & Niels Mailand
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Article
| Open AccessStructure of full-length ERGIC-53 in complex with MCFD2 for cargo transport
ERGIC-53 engages in the ER-to-Golgi transport of secretory and membrane proteins by unknown mechanisms. Here authors report a long flexible tetrameric structure of full-length ERGIC-53 complexed with its functional partner MCFD2 by cryo-EM.
- Satoshi Watanabe
- , Yoshiaki Kise
- & Kenji Inaba
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Article
| Open AccessStructure-based prediction and characterization of photo-crosslinking in native protein–RNA complexes
Feng et al. developed a computational method PxR3D-map to jointly analyze crosslinked nucleotides and amino acids in protein-RNA complexes, which revealed key structural features underlying photocrosslinking of protein and RNA in cells.
- Huijuan Feng
- , Xiang-Jun Lu
- & Chaolin Zhang
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Article
| Open AccessStructural characterization of the oligomerization of full-length Hantaan virus polymerase into symmetric dimers and hexamers
Hantaan virus polymerase is a central enzyme that performs hantavirus genome replication and transcription. Here, the authors unveil the structure of the full-length Hantaan virus polymerase in monomeric, dimeric and hexameric apo forms, revealing the multimerization capability of this enzyme.
- Quentin Durieux Trouilleton
- , Dominique Housset
- & Hélène Malet
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Article
| Open AccessFunctionalized graphene-oxide grids enable high-resolution cryo-EM structures of the SNF2h-nucleosome complex without crosslinking
Nucleosome-protein complexes stick to the air-water interface and denature upon plunge freezing for cryoEM. Here, authors Chio and Palovcak et al. develop EM grids that protect such complexes and use these grids to study the ATP-dependent chromatin remodeler SNF2h.
- Un Seng Chio
- , Eugene Palovcak
- & Yifan Cheng
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Article
| Open AccessAutomating data analysis for hydrogen/deuterium exchange mass spectrometry using data-independent acquisition methodology
Manual data mining for HDX-MS restricts the use of this biophysical technique to a small number of samples run by specialty labs. Enabled by data-independent acquisition methodology, the authors describe an approach that fully automates and standardizes the information extraction process, opening the door to new and challenging applications.
- Frantisek Filandr
- , Vladimir Sarpe
- & David C. Schriemer
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Article
| Open AccessViscosity-dependent control of protein synthesis and degradation
Xenopus egg extracts constitute a cell-like system for studying biochemical reactions. Here Chen and co-workers show that extract protein synthesis and degradation are differently affected by cytoplasmic concentration and viscosity.
- Yuping Chen
- , Jo-Hsi Huang
- & James E. Ferrell Jr.
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Article
| Open AccessProTInSeq: transposon insertion tracking by ultra-deep DNA sequencing to identify translated large and small ORFs
Identifying small proteins is challenging. ProTInSeq uses modified transposons to express markers inserted in-frame to protein-coding genes. This method identifies 153 unannotated small proteins in M. pneumoniae and additional proteomic information.
- Samuel Miravet-Verde
- , Rocco Mazzolini
- & Luis Serrano
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Article
| Open AccessAn artificial protein modulator reprogramming neuronal protein functions
Direct modulation of protein by artificial catalysts as enzyme mimetics remains hindered by the lack of highly efficient catalytic centers. Here, the authors present the development of artificial protein modulators (APROMs) with protein phosphatase-like characteristics, catalytically reprogram the biological function of α-synuclein.
- Peihua Lin
- , Bo Zhang
- & Daishun Ling
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Article
| Open AccessMicrotubule damage shapes the acetylation gradient
Microtubules are acetylated on the inside of their hollow lumen, a modification linked to their lifespan. Here, the authors show that damage holes act as entry points for a deacetylase to access the lumen, thereby locally counteracting acetylation.
- Mireia Andreu-Carbó
- , Cornelia Egoldt
- & Charlotte Aumeier
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Article
| Open AccessCryo-EM structures reveal how phosphate release from Arp3 weakens actin filament branches formed by Arp2/3 complex
Arp2/3 complex forms branched actin filaments for cell movements. Here, the authors report cryo-EM structures of branch junctions with ADP or ADPBeFx (to mimic γ-phosphate) bound to Arp3 to explain why γ-phosphate dissociation destabilizes branches.
- Sai Shashank Chavali
- , Steven Z. Chou
- & Charles V. Sindelar
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Article
| Open AccessSpecific pharmacological and Gi/o protein responses of some native GPCRs in neurons
G protein responses mediated by GPCRs may differ depending on their environment. Here, using highly sensitive Gi/o sensors, the authors reveal the specific pharmacological and Gi/o protein responses of some native GPCRs in neurons, and the influence of G protein composition.
- Chanjuan Xu
- , Yiwei Zhou
- & Jianfeng Liu
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Article
| Open AccessStructural basis for the modulation of MRP2 activity by phosphorylation and drugs
The ABC transporter MRP2/ABCC2 is a polyspecific efflux transporter of organic anions expressed in hepatocyte canalicular membranes. Dysfunction leads to Dubin-Johnson syndrome. Here the authors provide structural and biochemical evidence on the modulation of MRP2 by intracellular kinases and inhibition by therapeutic drugs.
- Tiziano Mazza
- , Theodoros I. Roumeliotis
- & Konstantinos Beis
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Article
| Open AccessStructure-guided engineering of biased-agonism in the human niacin receptor via single amino acid substitution
GPR109A is a prototypical GPCR and a key drug target for dyslipidemia. Here, the authors present cryo-EM structures of this receptor to elucidate agonist-binding and activation, and design receptor mutants with transducer-coupling-bias.
- Manish K. Yadav
- , Parishmita Sarma
- & Arun K. Shukla
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Article
| Open AccessA structural and dynamic visualization of the interaction between MAP7 and microtubules
Integrated structural data show that the MAP7 microtubule binding domain stabilizes the microtubule lattice through binding along protofilaments. Both strong and weak interactions between MAP7 and the lattice extend beyond a single tubulin dimer and include the tubulin C-terminal tails.
- Agnes Adler
- , Mamata Bangera
- & Marc Baldus
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Article
| Open AccessOrthoID: profiling dynamic proteomes through time and space using mutually orthogonal chemical tools
Proteomics at the organelle contact site remains challenging due to the spatial and temporal dynamics of proteins. Here, the authors developed OrthoID, a mutually orthogonal dual enzymatic proteomics approach to explore the proteome at the contact site of the endoplasmic reticulum and mitochondria.
- Ara Lee
- , Gihyun Sung
- & Kimoon Kim
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Article
| Open AccessStructure of the p53 degradation complex from HPV16
HPV’s E6 protein promotes cancer by degrading p53. This study reveals the cryoEM structure of HPV16 E6 in complex with E6AP and p53, highlighting their picomolar affinity and large protein-protein interaction interface.
- John C. K. Wang
- , Hannah T. Baddock
- & Aaron H. Nile
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Article
| Open AccessCryo-EM structure of cell-free synthesized human histamine 2 receptor/Gs complex in nanodisc environment
The study describes the molecular structure of the human histamine 2 receptor in active conformation and in complex with Gs heterotrimer, synthesized in a cell-free system and co-translationally inserted into preformed nanodiscs.
- Zoe Köck
- , Kilian Schnelle
- & Frank Bernhard
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Article
| Open AccessMirror-image ligand discovery enabled by single-shot fast-flow synthesis of D-proteins
Mirror-image phage display has the potential for high-throughput generation of biologically stable macrocyclic D-peptide binders but is hindered by the optimization required for D-protein chemical synthesis. Here, the authors report a general mirror-image phage display pipeline based on automated flow peptide synthesis and use it to prepare and characterize 12 L/D-protein pairs.
- Alex J. Callahan
- , Satish Gandhesiri
- & Bradley L. Pentelute
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Article
| Open AccessA co-assembly platform engaging macrophage scavenger receptor A for lysosome-targeting protein degradation
Targeted degradation of proteins has emerged as a powerful method for modulating protein homeostasis. Here, the authors develop LYTACAs, a modular supramolecular lysosome-targeting co-assembly system, as an effective platform for lysosomal degradation of extracellular and membrane proteins.
- Qian Wang
- , Xingyue Yang
- & Suwei Dong
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Article
| Open AccessEuglena’s atypical respiratory chain adapts to the discoidal cristae and flexible metabolism
Euglena gracilis is a model organism of the eukaryotic supergroup Discoba, single-celled organisms containing mitochondria with discoid cristae. Here, the authors report structures of Euglena’s transport chain supercomplex to reveal their distinctive architecture and working mechanisms.
- Zhaoxiang He
- , Mengchen Wu
- & Long Zhou
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Article
| Open AccessA SPLICS reporter reveals \({{{{{\boldsymbol{\alpha }}}}}}\)-synuclein regulation of lysosome-mitochondria contacts which affects TFEB nuclear translocation
Mitochondria-lysosome interactions are fundamental to cellular physiology. Here, the authors describe a genetically-encoded SPLICS reporter to study short- and long-juxtapositions between mitochondria and lysosomes.
- Flavia Giamogante
- , Lucia Barazzuol
- & Marisa Brini
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Article
| Open AccessSpatiotemporal and direct capturing global substrates of lysine-modifying enzymes in living cells
Here the authors report a strategy to directly capture substrates of lysine-modifying enzymes via post-translational modification (PTM)-acceptor residue crosslinking in living cells, enabling global profiling of substrates of PTM-enzymes and validation of PTM-sites in a straightforward manner.
- Hao Hu
- , Wei Hu
- & Xiao-Hua Chen
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Article
| Open AccessComputational redesign of a hydrolase for nearly complete PET depolymerization at industrially relevant high-solids loading
The application of the LCC variant of polyethylene terephthalate (PET) hydrolase for industrial degradation of PET has been hindered by the 10% of nonbiodegradable PET. Here, the authors use a computational strategy to engineer TurboPETase which outperforms other PETase variants and achieves nearly complete depolymerization of the postconsumer PET bottles at a high, industrially relevant, level of solids loading.
- Yinglu Cui
- , Yanchun Chen
- & Bian Wu
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Article
| Open AccessDynamics of activation in the voltage-sensing domain of Ciona intestinalis phosphatase Ci-VSP
Understanding the molecular basis of voltage-sensing is of great importance in biology. Here, the authors use computational analysis and simulations to reveal atomic level insights into the mechanism of an isolated voltage-sensing domain.
- Spencer C. Guo
- , Rong Shen
- & Aaron R. Dinner
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Article
| Open AccessStructural basis for regulated assembly of the mitochondrial fission GTPase Drp1
Structural and functional studies highlight the molecular regulation of assembling the mitochondrial division machinery. The core unit is closed, and specific interactions open this unit to facilitate assembly at the right place and time in cells.
- Kristy Rochon
- , Brianna L. Bauer
- & Jason A. Mears
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Article
| Open AccessBinding kinetics drive G protein subtype selectivity at the β1-adrenergic receptor
The authors show G protein subtype selectivity at the β1-adrenergic receptor is driven by the binding kinetics of ternary complex formation. Bound to G protein, the receptor adopts conformations that differ from its agonist-bound solution states.
- Andrew J. Y. Jones
- , Thomas H. Harman
- & Daniel Nietlispach
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Article
| Open AccessDynamic nucleolar phase separation influenced by non-canonical function of LIN28A instructs pluripotent stem cell fate decisions
The role of nucleolar phase separation in stem cell fate decision is not well understood. Here, the authors show that the nucleolus-localized LIN28A protein undergoes LLPS in mESCs and in vitro, and that pluripotency state conversion depends on this phase separation capacity.
- Tianyu Tan
- , Bo Gao
- & Jin Zhang
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Article
| Open AccessStructural basis for lysophosphatidylserine recognition by GPR34
GPR34 is a GPCR which has an immunomodulatory role and recognizes lysophosphatidylserine (LysoPS) as a putative endogenous ligand. Here, authors report two cryo-EM structures of human GPR34-Gi complex with one of two ligands bound: either the LysoPS analogue S3E-LysoPS, or its derivative M1.
- Tamaki Izume
- , Ryo Kawahara
- & Osamu Nureki
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Article
| Open AccessCryo-EM structure of the extracellular domain of murine Thrombopoietin Receptor in complex with Thrombopoietin
The haematopoietic cytokine thrombopoietin (Tpo) is the primary regulator of megakaryocyte and platelet numbers. Here authors present a structural and biochemical characterization of how Tpo binds to its receptor to induce signaling.
- Kaiseal T. G. Sarson-Lawrence
- , Joshua M. Hardy
- & Nadia J. Kershaw
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Article
| Open AccessTransport mechanism of human bilirubin transporter ABCC2 tuned by the inter-module regulatory domain
Human ABC transporter ABCC2 transports conjugated bilirubin from hepatocyte to bile duct, dysfunction of which causes Dubin-Johnson syndrome. Here, the authors provide structural insights into the substrate specificity of ABCC2 and the transport mechanism regulated by the R domain.
- Yao-Xu Mao
- , Zhi-Peng Chen
- & Yuxing Chen
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Article
| Open AccessRescue of mitochondrial import failure by intercellular organellar transfer
Mitochondrial biogenesis and maintenance relies on protein import from the cytosol. Here, authors show that import failure impacts organelle structure and dynamics. They also identify a rescue mechanism involving intercellular mitochondrial transfer.
- Hope I. Needs
- , Emily Glover
- & Ian Collinson
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Article
| Open AccessIdentification of potential aggregation hotspots on Aβ42 fibrils blocked by the anti-amyloid chaperone-like BRICHOS domain
This study identifies potential aggregation hotspots on the fibril surface of Alzheimer’s disease associated Aβ42 fibrils, which are blocked by the anti-amyloid chaperone-like domain BRICHOS.
- Rakesh Kumar
- , Tanguy Le Marchand
- & Axel Abelein
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Article
| Open AccessLocation-agnostic site-specific protein bioconjugation via Baylis Hillman adducts
Proteins labelled site-specifically with small molecules are valuable assets for chemical biology and drug development. Here, the authors report Baylis Hillman orchestrated protein aminothiol labelling (BHoPAL), a bioconjugation strategy for specific labelling of the 1,2-aminothiol moiety and combine it with a lipoic acid ligase-based technology to achieve labelling at any desired site within proteins.
- Mudassir H. Mir
- , Sangeeta Parmar
- & Dimpy Kalia
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Article
| Open AccessStructural and functional insights into the lipid regulation of human anion exchanger 2
Anion exchanger 2 (AE2), a widely expressed Cl- /HCO3 - exchanger, participates in the regulation of intracellular pH. Here, the authors present the structures of AE2 and uncover the regulatory mechanism of PIP2.
- Weiqi Zhang
- , Dian Ding
- & Yuxin Yin
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Article
| Open AccessStructure of the M. tuberculosis DnaK−GrpE complex reveals how key DnaK roles are controlled
Cryo-EM analysis reveals that the GrpE dimer of M. tuberculosis undergoes ratcheting motions when bound to an intact DnaK, thereby allosterically regulating DnaK’s nucleotide exchange and substrate release.
- Xiansha Xiao
- , Allison Fay
- & Huilin Li
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Article
| Open AccessMolecular switching in transcription through splicing and proline-isomerization regulates stress responses in plants
Transcription factor DREB2A interacts with Med25 to regulate stress responses. Here, the authors show that DREB2A uses splicing and proline-isomerization for this regulation and that proline cis-trans switching introduces structural frustration facilitating regulator exchange.
- Frederik Friis Theisen
- , Andreas Prestel
- & Karen Skriver
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Article
| Open AccessCochaperones convey the energy of ATP hydrolysis for directional action of Hsp90
The precise role of cochaperones and ATP hydrolysis in driving Hsp90’s chaperone cycle is largely unclear. Here, the authors use single-molecule FRET to show that several cochaperones are necessary to establish directionality in Hsp90’s conformational cycle.
- Leonie Vollmar
- , Julia Schimpf
- & Thorsten Hugel
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Article
| Open AccessLigand coupling mechanism of the human serotonin transporter differentiates substrates from inhibitors
The serotonin transporter, targeted by several medications, terminates neurotransmission by clearing serotonin from the synaptic cleft. Combining biochemical results with in silico data, the authors show the key interactions that initiate substrate transport.
- Ralph Gradisch
- , Katharina Schlögl
- & Thomas Stockner
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Article
| Open AccessAssembly of a unique membrane complex in type VI secretion systems of Bacteroidota
The type VI secretion system (T6SS) of Gram-negative bacteria is typically anchored to the cell envelope through a membrane complex (MC), but Bacteroidota appear to lack genes encoding canonical MC components. Here, Bongiovanni et al. identify the Bacteroidota MC and study its biogenesis and connections with the conserved T6SS components.
- Thibault R. Bongiovanni
- , Casey J. Latario
- & Eric Durand
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Article
| Open AccessMechanism of anion exchange and small-molecule inhibition of pendrin
Here the authors report structures of pendrin, an anion exchanger, in complex with its substrate Cl−, I−, or HCO3−, which reveal two anion binding sites in each protomer. The authors also identify binding sites of a pendrin inhibitor, niflumic acid.
- Lie Wang
- , Anthony Hoang
- & Ming Zhou
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Article
| Open AccessTon motor conformational switch and peptidoglycan role in bacterial nutrient uptake
Gram-negative bacteria rely on the Ton system for nutrient uptake. Here, authors uncover how the ExbD protein acts as a conformational switch and the function of peptidoglycan in order to energize this transport process across the outer membrane.
- Maximilian Zinke
- , Maylis Lejeune
- & Nadia Izadi-Pruneyre
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