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| Open AccessStructure and mechanism of NALCN-FAM155A-UNC79-UNC80 channel complex
NALCN channel mediates sodium leak currents and is essential for neuronal activity. Here authors uncover the mechanism of how UNC79 and UNC80 interact and promote the function of NALCN channel.
- Yunlu Kang
- & Lei Chen
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Article
| Open AccessMolecular insights into biogenesis of glycosylphosphatidylinositol anchor proteins
GPI-T catalyzes the committed step in GPI anchor protein biogenesis. Here, Xu et al. report the cryo-EM structure of the human GPI-T, revealing critical elements within an elongated, shared active site which is topologically arranged for substrate specificity.
- Yidan Xu
- , Guowen Jia
- & Dianfan Li
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Article
| Open AccessStructural basis of ion – substrate coupling in the Na+-dependent dicarboxylate transporter VcINDY
DASS carboxylate transporters linked to metabolic diseases couple the Na+ gradient to nutrient uptake. Here, the authors unravel the structural basis by which Na+ binding coordinates substrate interactions, revealing a distinct coupling mechanism.
- David B. Sauer
- , Jennifer J. Marden
- & Da-Neng Wang
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Article
| Open AccessMolecular basis for inhibiting human glucose transporters by exofacial inhibitors
Human glucose transporters (GLUTs), particularly GLUT1 and GLUT3, are potential anticancer therapy targets. Here, Nan Wang et al. use an engineered GLUT 3 variant to identify an exofacial GLUT3 inhibitor, SA47, and elucidate the drug’s inhibitory mechanism.
- Nan Wang
- , Shuo Zhang
- & Nieng Yan
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Article
| Open AccessSubstrate recognition and cryo-EM structure of the ribosome-bound TAC toxin of Mycobacterium tuberculosis
Toxin-antitoxin systems are widespread in bacteria. Here the authors present structures of M. tuberculosis HigBTAC alone and bound to the ribosome in the presence of native cspA mRNA, shedding light on its mechanism of translation inhibition.
- Moise Mansour
- , Emmanuel Giudice
- & Pierre Genevaux
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Article
| Open AccessTMEM16 scramblases thin the membrane to enable lipid scrambling
Lipid scrambling is required for many cellular processes but the lipid-protein interactions that occur during transport are unknown. Using cryoEM and biochemical assays the authors show that membrane thinning is critical for lipid flipping.
- Maria E. Falzone
- , Zhang Feng
- & Alessio Accardi
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Article
| Open AccessThe pocketome of G-protein-coupled receptors reveals previously untargeted allosteric sites
G-protein-coupled receptors bind endogenous ligands at sites that are frequently highly conserved. Here, authors computationally describe alternative allosteric pockets, several of which have not been targeted by synthetic ligands before.
- Janik B. Hedderich
- , Margherita Persechino
- & Peter Kolb
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Article
| Open AccessIdentification of oleoylethanolamide as an endogenous ligand for HIF-3α
Whether hypoxia-inducible factors (HIFs) can be directly regulated by endogenous small molecules is a long-standing question. Here authors identified the metabolite oleoylethanolamide as a HIF-3α ligand and further revealed its mechanism of action.
- Xiaotong Diao
- , Fei Ye
- & Dalei Wu
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Article
| Open AccessMolecular basis for cooperative binding and synergy of ATP-site and allosteric EGFR inhibitors
Acquired drug resistance is common during chemotherapy. Here, the authors describe the structural basis and molecular mechanism by which allosteric and clinically approved, ATP-competitive inhibitors of EGFR synergize to overcome resistance in lung cancer.
- Tyler S. Beyett
- , Ciric To
- & Michael J. Eck
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Article
| Open AccessCryo-EM structures of thylakoid-located voltage-dependent chloride channel VCCN1
VCCN1 is a plant homolog of bestrophin channels and tunes photoreaction as a voltage-gated anion channel at thylakoids. Here, authors report the cryo-EM structures and functional features of apple VCCN1, with insights into its activation mechanism.
- Tatsuya Hagino
- , Takafumi Kato
- & Osamu Nureki
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Article
| Open AccessStructure of the Arabidopsis guard cell anion channel SLAC1 suggests activation mechanism by phosphorylation
The anion channel SLAC1 controls stomatal closure upon phosphoactivation. Here via structural analysis and electrophysiology, the authors propose an inhibition-release model where phosphorylation causes dissociation of a cytosolic plug from the SLAC1 transmembrane domains to induce conformational change in the pore-forming helices.
- Yawen Li
- , Yinan Ding
- & Linfeng Sun
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Article
| Open AccessEPicker is an exemplar-based continual learning approach for knowledge accumulation in cryoEM particle picking
Many existing deep learning algorithms for particle picking are not predictable on unseen datasets. Here the authors report an exemplar-based continual learning approach, EPicker, enabling accumulation of new knowledge of cryoEM particle picking without catastrophic forgetting of old knowledge.
- Xinyu Zhang
- , Tianfang Zhao
- & Xueming Li
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Article
| Open AccessCofilactin filaments regulate filopodial structure and dynamics in neuronal growth cones
In this manuscript the authors show that Filopodia switch between bundles of fascin-crosslinked actin and cofilin-decorated filaments, which exclude fascin binding due to altered structure and packing, as well as affect filopodial searching dynamics.
- Ryan K. Hylton
- , Jessica E. Heebner
- & Matthew T. Swulius
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Article
| Open AccessCrystal structures of BMPRII extracellular domain in binary and ternary receptor complexes with BMP10
Mutations in BMPR2 is the major genetic cause for pulmonary arterial hypertension (PAH). Here by solving crystal structures of BMPRII in binary and ternary receptor complexes with BMP10, the authors report the molecular recognition between BMPRII and BMP10, and its implication in PAH.
- Jingxu Guo
- , Bin Liu
- & Wei Li
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Article
| Open AccessStructural basis for the synthesis of the core 1 structure by C1GalT1
The glycosyltransferase C1GalT1 directs a key step in protein O-glycosylation important for the expression of the cancer-associated Tn and T antigens. Here, the authors provide molecular insights into the function of C1GalT1 by solving the crystal structure of the Drosophila enzyme-substrate complex.
- Andrés Manuel González-Ramírez
- , Ana Sofia Grosso
- & Ramon Hurtado-Guerrero
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Article
| Open AccessMultivalent interactions essential for lentiviral integrase function
The authors determined high-resolution cryo-EM structures of the lentiviral intasome — the nucleoprotein complex that inserts viral DNA into a host chromosome — and show that the architecture comprising 16 integrase subunits is critical for its function.
- Allison Ballandras-Colas
- , Vidya Chivukula
- & Peter Cherepanov
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Article
| Open AccessStructural basis for the inhibition of IAPP fibril formation by the co-chaperonin prefoldin
Integrated kinetic and structural investigations reveal that the ubiquitous co-chaperonin prefoldin interacts with its coiled-coil helices on the islet amyloid polypeptide fibril surface and fibril ends to inhibit fibril elongation and secondary nucleation.
- Ricarda Törner
- , Tatsiana Kupreichyk
- & Jerome Boisbouvier
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Article
| Open AccessUnique binding pattern for a lineage of human antibodies with broad reactivity against influenza A virus
While most broadly neutralizing antibodies (bnAb) against Influenza virus target conserved conformational epitopes of the glycoprotein hemagglutinin (HA), Sun et al. characterize a lineage of bnAbs that neutralize group 1 and 2 strains. Structural characterization shows that antibody 28-12 binds a continuous epitope within H3 (group 2) but requires a conformational epitope for H1 (group 1) binding. Comparison of germline-reverted Ab and intermediate mutants provides evidence for an evolutionary adaptation from group 2 to group 1 strain.
- Xiaoyu Sun
- , Caixuan Liu
- & Bing Sun
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Article
| Open AccessActivation and allosteric regulation of the orphan GPR88-Gi1 signaling complex
GPR88 is an orphan GPCR and regulates diverse brain functions. Here, the authors report two structures of the human GPR88-Gi complex, showing an allosteric ligand directly involved in the interaction interface between the receptor and G-protein, and a density which may represent an endogenous ligand of GPR88.
- Geng Chen
- , Jun Xu
- & Yang Du
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Article
| Open AccessFormation of thyroid hormone revealed by a cryo-EM structure of native bovine thyroglobulin
Thyroid hormones are formed within the precursor Thyroglobulin by a poorly understood process. Here Marechal et al. report a cryo-EM structure of native bovine Thyroglobulin with nascent thyroid hormone formed at a predicted hormone synthesis site.
- Nils Marechal
- , Banyuhay P. Serrano
- & Charles J. Weitz
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Article
| Open AccessIn crystallo observation of three metal ion promoted DNA polymerase misincorporation
By observing DNA polymerase misincorporation with time-resolved crystallography, the authors visualize three-metal ion dependent polymerase catalysis and identify A-site metal-mediated primer alignment as a key step in nucleotide discrimination.
- Caleb Chang
- , Christie Lee Luo
- & Yang Gao
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Article
| Open AccessMechanism of integrin activation by talin and its cooperation with kindlin
The authors report here that talin and kindlin, the two key integrin binders and activators, are bridged by paxillin to induce microclustering of integrins to potently bind to multivalent extracellular ligand and trigger rapid cell attachment.
- Fan Lu
- , Liang Zhu
- & Jun Qin
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Article
| Open AccessMolecular basis of antibiotic self-resistance in a bee larvae pathogen
The authors show that the N-acetyltransferase PamZ acts as a self-resistance factor disabling the antibacterial paenilamicin that is produced by the honey bee larvae pathogen Paenibacillus larvae.
- Tam Dang
- , Bernhard Loll
- & Roderich D. Süssmuth
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Article
| Open AccessStructural insights into TRPV2 activation by small molecules
A non-selective calcium channel transient receptor potential vanilloid 2 (TRPV2) is a potential drug target. Here, the authors employ cryo-electron microscopy, in silico docking, and electrophysiology to identify a binding site for an activator 2-aminoethoxydiphenyl borate (2-APB) in this channel.
- Ruth A. Pumroy
- , Anna D. Protopopova
- & Vera Y. Moiseenkova-Bell
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Article
| Open AccessCrystal structures and insights into precursor tRNA 5’-end processing by prokaryotic minimal protein-only RNase P
HARP are member of protein-only RNase P, which catalyzes pre-tRNA 5’-end processing and maturation. Here, the authors present crystal structure and provide mechanistic insights into pre-tRNA binding and cleavage by HARP proteins.
- Yangyang Li
- , Shichen Su
- & Jianhua Gan
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Article
| Open AccessThree-dimensional structure determination of protein complexes using matrix-landing mass spectrometry
Mass spectrometry (MS) is a powerful tool for the structural characterization of protein complexes. Here the authors offer a path for direct integration of MS and electron microscopy with a MS approach that enables grid deposition and structural preservation of gaseous protein complex ions.
- Michael S. Westphall
- , Kenneth W. Lee
- & Joshua J. Coon
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Article
| Open AccessL-tyrosine-bound ThiH structure reveals C–C bond break differences within radical SAM aromatic amino acid lyases
ThiH is a radical SAM L-tyrosine lyase involved in the biosynthesis of the thiazole ring of vitamin B1. Here, the authors report the crystal structure of ThiH in complex with its L-tyrosine substrate, revealing an unexpected protonation state and tunneling effect that lowers the reaction energy barrier.
- Patricia Amara
- , Claire Saragaglia
- & Yvain Nicolet
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Article
| Open AccessCovalent narlaprevir- and boceprevir-derived hybrid inhibitors of SARS-CoV-2 main protease
Three covalent hybrid inhibitors of SARS-CoV-2 main protease (Mpro) have been designed and compared to Pfizer’s nirmatrelvir (PF-07321332), providing atomic and thermodynamic details of their binding to the enzyme, and antiviral potency.
- Daniel W. Kneller
- , Hui Li
- & Andrey Kovalevsky
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Article
| Open AccessA distinctive ligand recognition mechanism by the human vasoactive intestinal polypeptide receptor 2
Vasoactive intestinal polypeptide receptor 2 (VIP2R) is involved in immunity. Here, the authors report two cryo-EM structures of the VIP2R–Gs in complex with the endogenous peptide ligand PACAP27, revealing a unique interaction mode between PACAP27 and the receptor, stabilized by the N-terminal α-helix of VIP2R.
- Yingna Xu
- , Wenbo Feng
- & Ming-Wei Wang
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Article
| Open AccessA structural exposé of noncanonical molecular reactivity within the protein tyrosine phosphatase WPD loop
Inositol pyrophosphates (PP-IPs) regulate immunity and phosphate homeostasis. Here, the authors’ structural dissection of an Arabidopsis thaliana PP-IP phosphatase reveals that substrates drive their own hydrolysis and identifies a highly elusive metaphosphate-like reaction intermediate.
- Huanchen Wang
- , Lalith Perera
- & Stephen B. Shears
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Article
| Open AccessStructure of ATP synthase under strain during catalysis
CryoEM of mitochondrial ATP synthase frozen during rotary catalysis reveals dramatic conformational changes in the peripheral stalk subcomplex, which enable the enzyme’s efficient synthesis of ATP.
- Hui Guo
- & John L. Rubinstein
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Article
| Open AccessMagic angle spinning NMR structure of human cofilin-2 assembled on actin filaments reveals isoform-specific conformation and binding mode
Despite their relevance as regulators of actin severing and filament disassembly, few structural insights into the mechanism of cofilin-isoform-specific severing activity are reported. Here, the authors provide structural insights towards actin severing activity by human cofilin-2 obtained by MAS NMR and all-atom MD simulations. The results reveal an isoform-specific binding mode unique to CFL2 that may be related to its potent severing properties in-vivo.
- Jodi Kraus
- , Ryan W. Russell
- & Tatyana Polenova
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Article
| Open AccessStructure, gating, and pharmacology of human CaV3.3 channel
T-type calcium channels are implicated in many diseases. Here, multiple structures of CaV3.3 channel elucidate molecular mechanisms of T-type CaV channels activation at low voltage and interaction with different clinically used channel blockers.
- Lingli He
- , Zhuoya Yu
- & Yan Zhao
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Article
| Open AccessStructural insights into the peptide selectivity and activation of human neuromedin U receptors
Neuromedin U receptors (NMURs) are potential drug targets for obesity and inflammatory disorders. Here, the authors report structural basis for neuromedin recognition and activation mechanism of NMURs.
- Chongzhao You
- , Yumu Zhang
- & Yi Jiang
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Article
| Open AccessStructural basis for the assembly and quinone transport mechanisms of the dimeric photosynthetic RC–LH1 supercomplex
Bacterial photosynthesis reflects the early stages of the evolution of photosynthesis. Here, the authors present a systematic study of the cryo-EM structures of the dimeric light harvesting–reaction center complexes and assembly variants from Rhodobacter sphaeroides, which delineated a hierarchical assembly pathway and quinone transport routes of the dimeric photosynthetic RC–LH1 core complex.
- Peng Cao
- , Laura Bracun
- & Lu-Ning Liu
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Article
| Open AccessThe crystal structure of iC3b-CR3 αI reveals a modular recognition of the main opsonin iC3b by the CR3 integrin receptor
Complement activation on foreign cell surfaces leads to the generation of complement opsonins, which activate complement receptor type 3 (CR3) and pathogen clearance by macrophages. Here, the authors reveal structural basis of the interaction between human opsonin iC3b and the von Willebrand A inserted domain of the α chain of CR3.
- Francisco J. Fernández
- , Jorge Santos-López
- & M. Cristina Vega
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Article
| Open AccessInsights into the inhibition of type I-F CRISPR-Cas system by a multifunctional anti-CRISPR protein AcrIF24
Phages use anti-CRISPR proteins (Acrs) to counteract the bacterial CRISPR-Cas systems. Here, the authors characterize AcrIF24, which functions as an Aca (Acr-associated) to repress and regulate its own transcription, dimerizes the Csy complex, blocks the hybridization of target DNA, and tethers non-sequence-specific DNA to the Csy complex.
- Lingguang Yang
- , Laixing Zhang
- & Yue Feng
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Article
| Open AccessFunctional control of a 0.5 MDa TET aminopeptidase by a flexible loop revealed by MAS NMR
Motion is key to enzymatic catalysis. Gauto et al. show that a flexible loop region is crucial for the function of an aminopeptidase and show that magic-angle spinning NMR provides atomic-level quantitative insights in this very large complex.
- Diego F. Gauto
- , Pavel Macek
- & Paul Schanda
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Article
| Open AccessAsymmetric structure of the native Rhodobacter sphaeroides dimeric LH1–RC complex
Rhodobacter sphaeroides is a model organism for studying bacterial photosynthesis. Here, the authors present structures of its native dimeric and a protein-U-lacking monomeric light-harvesting-reaction center complexes, which reveal asymmetric features for the dimer and an altered shape for the monomer.
- Kazutoshi Tani
- , Ryo Kanno
- & Zheng-Yu Wang-Otomo
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Article
| Open AccessWaffle Method: A general and flexible approach for improving throughput in FIB-milling
Here the authors describe the Waffle Method, aimed at increasing the throughput of and solves several challenges present in cryo-FIB/SEM sample preparation for cryo-ET analysis — the highest-resolution method for obtaining 3D views of native biological specimens in-situ.
- Kotaro Kelley
- , Ashleigh M. Raczkowski
- & Alex J. Noble
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Article
| Open AccessActivation of the essential kinase PDK1 by phosphoinositide-driven trans-autophosphorylation
The essential protein kinase PDK1 is activated by phospoinositide-mediated dimerization and trans-autophosphorylation. Here, the authors show that in the absence of PIP3 or PI(3,4)P2 phosphoinositides, PDK1 is maintained in an inactive, autoinhibited conformation in the cytosol.
- Aleksandra Levina
- , Kaelin D. Fleming
- & Thomas A. Leonard
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Article
| Open AccessStructural basis for PoxtA-mediated resistance to phenicol and oxazolidinone antibiotics
PoxtA confers resistance to ribosome-targeting oxazolidinone (linezolid) and chloramphenicol antibiotics. Here, Crowe-McAuliffe et al. provide structural insights into how binding of PoxtA to the ribosome indirectly promotes drug dissociation.
- Caillan Crowe-McAuliffe
- , Victoriia Murina
- & Vasili Hauryliuk
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Article
| Open AccessStructural basis for the mechanisms of human presequence protease conformational switch and substrate recognition
Presequence protease (PreP) is essential to mitochondrial proteostasis. This study leverages advanced vitrification techniques to solve cryoEM structures of apo- and substrate-bound PreP and integrates these data with other analysis to reveal key stages and mechanistic insights of the PreP catalytic cycle.
- Wenguang G. Liang
- , Juwina Wijaya
- & Wei-Jen Tang
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Article
| Open AccessStructure-based design of stabilized recombinant influenza neuraminidase tetramers
Influenza virus neuraminidase (NA) is a drug target and a potential vaccine antigen. Here, the authors provide a detailed analysis of the conformational stability of NA, and show how expression and stability of recombinant NA antigens can be strengthened through structure-based design.
- Daniel Ellis
- , Julia Lederhofer
- & Masaru Kanekiyo
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Article
| Open AccessCryo-EM structures of a LptDE transporter in complex with Pro-macrobodies offer insight into lipopolysaccharide translocation
Lateral opening of the LptDE transporter in the outer membrane of Gram-negative bacteria is necessary for insertion of lipopolysaccharides. Here, Botte et al. report a cryo-EM structure of a partially opened LptDE transporter, in complex with rigid chaperones derived from nanobodies.
- Mathieu Botte
- , Dongchun Ni
- & Michael Hennig
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Article
| Open AccessStructural basis for the SUMO protease activity of the atypical ubiquitin-specific protease USPL1
USPL1 is a non-canonical member of the ubiquitin-specific protease (USP) family with activity toward SUMO instead of ubiquitin. Here, the authors present a crystal structure of USPL1 bound to SUMO2, revealing how this enzyme has evolved to bind SUMO as an example of divergent evolution in the USP family.
- Ying Li
- , Nathalia Varejão
- & David Reverter
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Article
| Open AccessExploration of the dynamic interplay between lipids and membrane proteins by hydrostatic pressure
Direct information on the dynamic interplay between membrane proteins and lipids is scarce. Here the authors report a detailed description of these close relationships by combining lipid nanodiscs and high-pressure NMR. They report the link between pressure and lipid compositions to the conformational landscape of the β-barrel OmpX and the α-helical BLT2 G Protein-Coupled Receptor in nanodiscs.
- Alexandre Pozza
- , François Giraud
- & Laurent J. Catoire
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Article
| Open AccessStructural basis of FPR2 in recognition of Aβ42 and neuroprotection by humanin
The formyl peptide receptor 2 (FPR2) is involved in the pathogenesis of Alzheimer’s disease. Structures of FPR2 bound to Aβ42, humanin, or formyl peptides offer insight into Aβ42 neurotoxicity, humanin neuroprotection, and FPR ligand selectivity
- Ya Zhu
- , Xiaowen Lin
- & Beili Wu
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Article
| Open AccessAssembly mechanism of the pleomorphic immature poxvirus scaffold
Immature poxviruses are characterized by nonicosahedral semiordered protein scaffolds critical for morphogenesis. Here, the authors use cryo-EM structures of Vaccinia virus D13 scaffold intermediates to explain their assembly mechanism.
- Jaekyung Hyun
- , Hideyuki Matsunami
- & Matthias Wolf