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| Open AccessInadequate structural constraint on Fab approach rather than paratope elicitation limits HIV-1 MPER vaccine utility
It is still unclear why HIV-1 vaccines targeting MPER induce antibodies that fail to bind HIV. Here, the authors show that antibodies targeting membrane-proximal linear epitopes of virion spike proteins must generate relevant antibody paratopes and approach angles to ligate their quarry in a topologically restricted site.
- Kemin Tan
- , Junjian Chen
- & Mikyung Kim
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Article
| Open AccessStructural insights into the modulation of coronavirus spike tilting and infectivity by hinge glycans
In this work, the authors combine cryo-electron tomography of vitrified virions, mass spectrometry, modeling, molecular dynamics and infectivity assay and report that a hinge glycan on viral spike protein influences virus infection and immune evasion.
- David Chmielewski
- , Eric A. Wilson
- & Wah Chiu
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Article
| Open AccessStructural basis of peptide secretion for Quorum sensing by ComA
Quorum sensing is a regulatory mechanism controlling bacterial signaling and ComA, a conserved efflux pump, is responsible for the maturation and secretion of peptide signals. Here, authors determine the 3D structure and demonstrate its function as an ABC transporter.
- Lin Yu
- , Xin Xu
- & Min Luo
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Article
| Open AccessRNA recognition by Npl3p reveals U2 snRNA-binding compatible with a chaperone role during splicing
Here the authors identify the sequence bound by Npl3 and solve the structure of the complex using NMR. Npl3 binds directly to the U2 snRNA and melt the stem-loop I, suggesting a chaperoning role during spliceosome active site formation.
- Ahmed Moursy
- , Antoine Cléry
- & Frédéric H.-T. Allain
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Article
| Open AccessStructure of a heteropolymeric type 4 pilus from a monoderm bacterium
Here, Anger et al. report the structure of the type 4 pilus (T4P) from Streptococcus sanguinis. They show that the T4P architecture seen in diderm bacteria – where the N-terminal α-helices of pilin subunits are partially unfolded upon polymerisation – is conserved in distant monoderm species.
- Robin Anger
- , Laetitia Pieulle
- & Rémi Fronzes
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Article
| Open AccessDual function of OmpM as outer membrane tether and nutrient uptake channel in diderm Firmicutes
Outer membrane tethering is important for cell envelope integrity in diderm bacteria. Here, the authors present structures and functional analyses of the stalked porin OmpM, which is the main outer membrane tethering system within the Terrabacteria.
- Augustinas Silale
- , Yiling Zhu
- & Bert van den Berg
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Article
| Open AccessEnzymatic β-elimination in natural product O- and C-glycoside deglycosylation
Biological degradation of glycosides involves, alongside hydrolysis, β-elimination for glycosidic bond cleavage. Here, the authors report an O-glycoside β-eliminase from Agrobacterium tumefaciens that converts the C3-oxidized O-β-d-glucoside of phloretin into the aglycone and the 2-hydroxy-3-keto-d-glycal elimination product, and suggest convergent evolution of β-eliminase active sites for the cleavage of natural product 3-keto-O-glycosides.
- Johannes Bitter
- , Martin Pfeiffer
- & Bernd Nidetzky
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Article
| Open AccessStructural basis for ligand recognition and signaling of hydroxy-carboxylic acid receptor 2
Niacin is used to treat cardiovascular disease through its activation of the GPCR HCAR2. Here, the authors present cryo-EM structures of HCAR2 bound to niacin and other drug-like small molecules, which explain the basis of HCAR2 ligand recognition.
- Jae-Hyun Park
- , Kouki Kawakami
- & Sam-Yong Park
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Article
| Open AccessElevator-like movements of prestin mediate outer hair cell electromotility
Probing the molecular dynamics of the membrane motor, prestin, with biophysical measures and MD simulations, Kuwabara et al. find that an elevator-like domain movement across the membrane produces the unique piezoelectric behavior.
- Makoto F. Kuwabara
- , Bassam G. Haddad
- & Dominik Oliver
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Article
| Open AccessStructural adaptation of fungal cell wall in hypersaline environment
Solid-state NMR snapshots of Aspergillus sydowii and other halophilic fungal species reveal the structural rearrangement of polysaccharides and proteins, which create a thick, stiff and hydrophobic cell wall to withstand external stress and thrive in hypersaline environment
- Liyanage D. Fernando
- , Yordanis Pérez-Llano
- & Tuo Wang
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Article
| Open AccessStructure and function of the EA1 surface layer of Bacillus anthracis
S-layers form continuous protein lattices on the surface of bacteria. Here, authors use S-layer depolymerizing nanobodies to solve the structure of the EA1 S-layer in the pathogen Bacillus anthracis and show its role as cell wall supportive structure”
- Adrià Sogues
- , Antonella Fioravanti
- & Han Remaut
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Article
| Open AccessStructural basis for the toxicity of Legionella pneumophila effector SidH
Legionella pneumophila secretes hundreds of effectors to facilitate infection. Here, Sharma et al show that the virulence effector SidH adopts a unique α-helical conformation, leading to toxicity via tRNA binding site and resolve the structural basis of SidH regulation through ubiquitination.
- Rahul Sharma
- , Michael Adams
- & Sagar Bhogaraju
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Article
| Open AccessDNAJB6 mutants display toxic gain of function through unregulated interaction with Hsp70 chaperones
Here the authors characterize DNAJB6 mutants found in LGMDD1 patients. They show that these mutants retain aggregation-prevention activity, but have impaired regulation of Hsp70 binding, uncontrollably recruiting Hsp70s, depleting the chaperone levels and disrupting proteostasis.
- Meital Abayev-Avraham
- , Yehuda Salzberg
- & Rina Rosenzweig
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Article
| Open AccessStructural basis for stabilisation of the RAD51 nucleoprotein filament by BRCA2
Here the authors report the cryoEM structure of the RAD51 nucleoprotein filament bound to the C-terminal TR2 domain of BRCA2. The structure explains how BRCA2 stabilises the filament and uncovers a conserved mechanism of filament binding by recombination mediators.
- Robert Appleby
- , Luay Joudeh
- & Luca Pellegrini
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Article
| Open AccessRecognition and reprogramming of E3 ubiquitin ligase surfaces by α-helical peptides
Identification of molecules that induce novel interactions between proteins has been limited by the complexity of rationally designing interactions. The authors report a method to discover molecular glue-like “trimerizers” based on α-helically constrained peptides that can co-opt the surfaces of E3 ubiquitin ligases to bind therapeutically important proteins.
- Olena S. Tokareva
- , Kunhua Li
- & John H. McGee
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Article
| Open AccessThe structure of a hibernating ribosome in a Lyme disease pathogen
Ribosomes are prime targets for antibiotics in pathogenic bacteria. Here, cryo-electron microscopy reveals features in the Borrelia burgdorferi ribosome that provide insights into ribosome evolution, dormancy, and antibiotic binding.
- Manjuli R. Sharma
- , Swati R. Manjari
- & Nilesh K. Banavali
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Article
| Open AccessCryo-EM structure of human O-GlcNAcylation enzyme pair OGT-OGA complex
The single pair of enzymes in human, OGT and OGA, mediates protein OGlcNAcylation cycle. Here, authors provide cryo-EM structures of OGT-OGA complex, revealing how OGT selects native substrates and the mutual inhibition mechanism between OGT and OGA.
- Ping Lu
- , Yusong Liu
- & Haishan Gao
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Article
| Open AccessDIAPH1-MFN2 interaction regulates mitochondria-SR/ER contact and modulates ischemic/hypoxic stress
Proximity between mitochondria and endoplasmic reticulum regulates mitochondria fitness and is adversely affected by tissue ischemia. This work reveals that Diaphanous1-Mitofusin2 interaction regulates this proximity and impairs recovery in ischemia.
- Gautham Yepuri
- , Lisa M. Ramirez
- & Ravichandran Ramasamy
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Article
| Open AccessA marine cryptochrome with an inverse photo-oligomerization mechanism
Cryptochromes are important components of biological clocks. Here, the authors uncover that a cryptochrome that enables synchronization of the reproduction of marine worms to the lunar cycle uses an inverse photo-oligomerization mechanism.
- Hong Ha Vu
- , Heide Behrmann
- & Elmar Behrmann
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Article
| Open AccessStructural titration reveals Ca2+-dependent conformational landscape of the IP3 receptor
Inositol 1,4,5-trisphosphate receptors (IP3Rs) are intracellular Ca2+ channels that produce Ca2+ oscillations in response to GPCR and RTK activation. Here, Paknejad et al. resolve the conformational landscape of IP3Rs that gives rise to the biphasic dependence on Ca2+ for channel activity.
- Navid Paknejad
- , Vinay Sapuru
- & Richard K. Hite
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Article
| Open AccessMechanism of synergistic activation of Arp2/3 complex by cortactin and WASP-family proteins
Arp2/3 complex is activated by nucleation promoting factors (NPFs) to form actin branches that are stabilized by cortactin. Here, the authors show that NPFs and cortactin activate Arp2/3 complex synergistically by helping recruit the complex to F-actin and by stabilizing its active conformation
- Fred E. Fregoso
- , Malgorzata Boczkowska
- & Roberto Dominguez
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Article
| Open AccessMultivalent Tau/PSD-95 interactions arrest in vitro condensates and clusters mimicking the postsynaptic density
Cognitive impairment in Alzheimer’s disease is associated with Tau at the postsynapse. We show that multivalent Tau interactions arrest in vitro condensates and clusters mimicking the postsynaptic density that may result in synaptic dysfunction.
- Zheng Shen
- , Daxiao Sun
- & Markus Zweckstetter
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Article
| Open AccessPhosphorylation-dependent pseudokinase domain dimerization drives full-length MLKL oligomerization
How the necroptosis executioner, MLKL, converts to a killer form has been mysterious. Here, authors show RIPK3-mediated phosphorylation of human MLKL is the cue for pseudokinase domain dimerization before assembly of pro-necroptotic MLKL tetramers.
- Yanxiang Meng
- , Sarah E. Garnish
- & James M. Murphy
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Article
| Open AccessMechanism of substrate hydrolysis by the human nucleotide pool sanitiser DNPH1
Inactivation of DNPH1 leads to hmdU incorporation into DNA, sensitising BRCA-deficient cells to PARP inhibitors. Crystal structures of DNPH1 bound to hmdU monophosphate reveal a two-step mechanism for hydrolysis via a glycosyl-enzyme intermediate.
- Neil J. Rzechorzek
- , Simone Kunzelmann
- & Stephen C. West
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Article
| Open AccessDe novo design of knotted tandem repeat proteins
This study reports the successful de novo design of a trefoil knotted protein fold for which the crystal structure agrees closely with the intended trefoil knot topology.
- Lindsey A. Doyle
- , Brittany Takushi
- & Philip Bradley
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Article
| Open AccessRecognition and coacervation of G-quadruplexes by a multifunctional disordered region in RECQ4 helicase
In this work, the authors report a three-step charge-driven coacervation model involving dynamic complexes between a positively charged IDR of human RECQ4 and G-quadruplexes. The IDR also interacts with Replication Protein A, implying RECQ4’s regulatory role.
- Anna C. Papageorgiou
- , Michaela Pospisilova
- & Konstantinos Tripsianes
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Article
| Open AccessStaphylococcus aureus sacculus mediates activities of M23 hydrolases
In this work, the authors provide structural insights into the interaction of two evolutionarily related peptidoglycan hydrolases, lysostaphin and LytM with S. aureus sacculus, and propose a model in which PG crosslinking affects their activity differently.
- Alicja Razew
- , Cedric Laguri
- & Jean-Pierre Simorre
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Article
| Open AccessSIgA structures bound to Streptococcus pyogenes M4 and human CD89 provide insights into host-pathogen interactions
Here, the authors used cryo-EM to explore secretory Immunoglobulin A interactions with bacterial and host receptors, uncovering unexpected binding stoichiometry and unappreciated functional consequences relevant to understanding host-pathogen interactions.
- Qianqiao Liu
- & Beth M. Stadtmueller
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Article
| Open AccessHierarchical organization and assembly of the archaeal cell sheath from an amyloid-like protein
Cellular cryoET reveals how an amyloid-like protein of the prototypical archaeon, Methanospirillum hungatei, oligomerizes into a ring containing a giant 2700-strand β sheet, and how rings stack into hoops and into the cylindrical sheath of the cell.
- Hui Wang
- , Jiayan Zhang
- & Z. Hong Zhou
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Article
| Open AccessHow myosin VI traps its off-state, is activated and dimerizes
Canon et al. offer insights into the auto-inhibition and activation of the minus-end directed motor myosin VI. The work highlights how differential relief of auto-inhibition allows for fine control of myosin VI activity in vivo.
- Louise Canon
- , Carlos Kikuti
- & Anne Houdusse
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Article
| Open AccessStructural insights into the agonists binding and receptor selectivity of human histamine H4 receptor
Histamine receptor H4R is implicated in chronic inflammatory diseases, such as asthma, arthritis, and atopic dermatitis. Here, the authors determined the first cryo-EM structure of the histamine H4 receptor, providing valuable structural insights for the design of drugs targeting H4R in chronic inflammatory diseases.
- Dohyun Im
- , Jun-ichi Kishikawa
- & So Iwata
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Article
| Open AccessInsights into the missing apiosylation step in flavonoid apiosides biosynthesis of Leguminosae plants
Apiosides are plant bioactive natural products containing apiose, but the details of the key apiosylation reaction in their biosynthesis are missing. Here, the authors identify the apiosyltransferase GuApiGT that could efficiently catalyze 2″-O-apiosylation of flavonoid glycosides, solve its crystal structure and obtain mutants with altered sugar selectivity.
- Hao-Tian Wang
- , Zi-Long Wang
- & Min Ye
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Article
| Open AccessA conformation-locking inhibitor of SLC15A4 with TASL proteostatic anti-inflammatory activity
The authors identify feeblin, an inhibitory compound of the proinflammatory TLR7/8/9-IRF5 pathway with therapeutic potential, which acts by binding SLC15A4 via an allosteric mechanism mediating degradation of its signaling partner TASL.
- Andras Boeszoermenyi
- , Léa Bernaleau
- & Giulio Superti-Furga
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| Open AccessStructural basis for recruitment of TASL by SLC15A4 in human endolysosomal TLR signaling
Three structures of human SLC15A4 are presented in the outward-facing apo monomeric and dimeric states and the inward-facing TASL-bound state, revealing the molecular mechanism of SLC15A4-mediated TASL recruitment in human endolysosomal TLRs signalling.
- Xudong Chen
- , Min Xie
- & Maojun Yang
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Article
| Open AccessLactate dehydrogenase D is a general dehydrogenase for D-2-hydroxyacids and is associated with D-lactic acidosis
Currently the structure and biological function of Lactate Dehydrogenase D (LDHD) are unclear. Here the authors report the structure of LDHD bound with various ligands and show that LDHD is a general dehydrogenase for D-2-hydroxyacids with small to moderate-size hydrophobic moieties and investigate loss-of-function mutations that play an important role in D-lactic acidosis.
- Shan Jin
- , Xingchen Chen
- & Jianping Ding
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Article
| Open AccessAn allosteric switch between the activation loop and a c-terminal palindromic phospho-motif controls c-Src function
Protein kinase transition between different conformational states is controlled by autophosphorylation. Here, the authors demonstrate that the c-terminal Tyr530 is a de facto c-Src autophosphorylation site and identify a critical c-terminal palindromic phospho-motif that controls the interplay between substrate and enzyme-acting kinases during autophosphorylation.
- Hipólito Nicolás Cuesta-Hernández
- , Julia Contreras
- & Iván Plaza-Menacho
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Article
| Open AccessStreamlined structure determination by cryo-electron tomography and subtomogram averaging using TomoBEAR
Cryo-electron tomography (cryo-ET) enables structural analysis of molecules in situ, but the process is demanding. Here, authors report a software package, TomoBEAR, that streamlines data processing yielding high resolution structures with minimal user input.
- Nikita Balyschew
- , Artsemi Yushkevich
- & Mikhail Kudryashev
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Article
| Open AccessDistantly related Alteromonas bacteriophages share tail fibers exhibiting properties of transient chaperone caps
Receptor binding proteins in bacteriophage tails mediate host recognition and thus infectivity. Here Gonzalez et al. identify a receptor binding module shared by different phages that all use receptor binding tail fibers that are transiently capped by their chaperones.
- Rafael Gonzalez-Serrano
- , Riccardo Rosselli
- & Matthew Dunne
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Article
| Open AccessA single nanobody neutralizes multiple epochally evolving human noroviruses by modulating capsid plasticity
GII.4 human noroviruses cause pandemic gastroenteritis and undergo epochal evolution. This study shows that a single Llama-derived nanobody neutralizes multiple GII.4 variants using a mechanism by targeting capsid plasticity.
- Wilhelm Salmen
- , Liya Hu
- & B. V. Venkataram Prasad
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Article
| Open AccessDesign, structure and plasma binding of ancestral β-CoV scaffold antigens
Development of vaccines remains challenging because viral antigens can be unstable or aggregate. Here, authors present ancestral sequence reconstruction as a method to generate stable and soluble antigens using exclusively available sequence information.
- David Hueting
- , Karen Schriever
- & Per-Olof Syrén
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Article
| Open AccessStructural basis for the unique molecular properties of broad-range phospholipase C from Listeria monocytogenes
The bacterium Listeria monocytogenes possesses two major virulence factors, broad-range phospholipase C (LmPC-PLC) and the pore-forming toxin listeriolysin O (LLO). Here, authors perform structural and biochemical analysis of LmPC-PLC and show that unique structural features enable self-regulation of its enzymatic activity and positive synergy with the pore-forming toxin listeriolysin O.
- Nejc Petrišič
- , Maksimiljan Adamek
- & Marjetka Podobnik
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Article
| Open AccessStructure of the transcription open complex of distinct σI factors
Here the authors show that σI factors encompass a unique, hitherto-unknown recognition mode of bacterial transcriptional promoters and represent a new distinctive class of σ70-family σ factors for bacterial transcription.
- Jie Li
- , Haonan Zhang
- & Ping Zhu
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Article
| Open AccessStructural insights into the allosteric inhibition of P2X4 receptors
Cryo-EM structures revealed how chemical compounds bind to and inhibit P2X4 receptors involved in neuropathic pain, potentially facilitating the design of drugs targeting P2X4 receptors.
- Cheng Shen
- , Yuqing Zhang
- & Motoyuki Hattori
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Article
| Open AccessStructural basis for triacylglyceride extraction from mycobacterial inner membrane by MFS transporter Rv1410
Triacylglycerides help to secure the impermeability of mycobacterial cell envelope to some drugs. Here, authors solve the structure of the triacylglyceride transporter Rv1410 and proposed a molecular mechanism for triacylglyceride extraction.
- Sille Remm
- , Dario De Vecchis
- & Markus A. Seeger
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Article
| Open AccessMolecular mechanism of decision-making in glycosaminoglycan biosynthesis
Heparan sulfate (HS) and chondroitin sulfate (CS) are different glycosaminoglycan chains that are attached to core proteins via the same linker tetrasaccharide, and it was unclear how core proteins are specifically modified with HS or CS. Here, the authors determine that the CS-initiating glycosyltransferase CSGALNACT2 is promiscuous, whereas the HS-initiating glycosyltransferase EXTL3 selects only certain core proteins for modification.
- Douglas Sammon
- , Anja Krueger
- & Erhard Hohenester
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Article
| Open AccessIntegrative solution structure of PTBP1-IRES complex reveals strong compaction and ordering with residual conformational flexibility
An integrated structural biology approach is utilized to elucidate the solution structure of the polypyrimidine-tract binding protein 1 (PTBP1/hnRNP I) complexed with an internal ribosome entry site (IRES) RNA fragment from encephalomyocarditis virus (EMCV).
- Georg Dorn
- , Christoph Gmeiner
- & Frédéric H.-T. Allain
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Article
| Open AccessCryo-EM structure of cyanophage P-SCSP1u offers insights into DNA gating and evolution of T7-like viruses
Here the authors unveil the assembly of a cyanophage in its native form, providing insights into DNA gating and infection process of tailed phages. They proposed structure-based analysis for virus evolution and classification.
- Lanlan Cai
- , Hang Liu
- & Shangyu Dang
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Article
| Open AccessCryo-electron microscopy of IgM-VAR2CSA complex reveals IgM inhibits binding of Plasmodium falciparum to Chondroitin Sulfate A
Placental malaria parasite binds to host IgM however its functional importance was not understood. Here, authors resolved structure of IgM-VAR2CSA complex using cryo-EM to show that IgM masks VAR2CSA and inhibits its binding to receptor.
- Reetesh Raj Akhouri
- , Suchi Goel
- & Ulf Skoglund
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Article
| Open AccessKRAS G12V neoantigen specific T cell receptor for adoptive T cell therapy against tumors
Recent evidence suggests that KRAS mutations can be source of neoantigens and elicit T cell responses. Here the authors report the identification and characterization of KRAS-G12V specific TCRs for adoptive T cell immunotherapy.
- Dan Lu
- , Yuan Chen
- & George F. Gao