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Structural and molecular basis of choline uptake into the brain by FLVCR2
FLVCR2 is expressed in the blood–brain barrier of mouse and human, and is the major mediator of choline uptake into the brain.
- Rosemary J. Cater
- , Dibyanti Mukherjee
- & Filippo Mancia
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Promiscuous G-protein activation by the calcium-sensing receptor
Structures of the human calcium-sensing receptor can be bound into complex with G proteins from three different Gα subtypes while maintaining G-protein-binding specificity.
- Hao Zuo
- , Jinseo Park
- & Qing R. Fan
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| Open AccessCryo-EM structures of RAD51 assembled on nucleosomes containing a DSB site
Cryo-electron microscopy structures of human RAD51 in complex with the nucleosome show that RAD51 can adopt two conformations—rings and filaments—and reveal how RAD51 binds to the nucleosome through its N-terminal lobe domain.
- Takuro Shioi
- , Suguru Hatazawa
- & Hitoshi Kurumizaka
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Structural insights into vesicular monoamine storage and drug interactions
Monoamines and neurotoxicants share a binding pocket in VMAT1 featuring polar sites for specificity and a wrist-and-fist shape for versatility, and monoamine enrichment in storage vesicles arises from dominant import via favoured lumenal-open transition of VMAT1 and protonation-precluded binding during its cytoplasmic-open transition.
- Jin Ye
- , Huaping Chen
- & Weikai Li
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Time-resolved cryo-EM of G-protein activation by a GPCR
Time-resolved cryo-EM is used to capture structural transitions during G-protein activation stimulated by a G-protein-coupled receptor.
- Makaía M. Papasergi-Scott
- , Guillermo Pérez-Hernández
- & Georgios Skiniotis
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| Open AccessTargeted protein degradation via intramolecular bivalent glues
Studies using genetic screening, biophysical characterization and structural reconstitution elucidate the mechanism of action and enable rational design of a new class of functional compounds that glue target proteins to E3 ligases via intramolecularly bridging two domains to enhance intrinsic protein–protein interactions and promote target ubiquitination and degradation.
- Oliver Hsia
- , Matthias Hinterndorfer
- & Alessio Ciulli
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| Open AccessThe UFM1 E3 ligase recognizes and releases 60S ribosomes from ER translocons
Attachment of the ubiquitin-like modifier UFM1 to 60S ribosomes has a critical function in the release and recycling of stalled or terminated ribosomes from the endoplasmic reticulum membrane.
- Linda Makhlouf
- , Joshua J. Peter
- & Yogesh Kulathu
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Allosteric modulation and G-protein selectivity of the Ca2+-sensing receptor
Cryo-electron microscopy structures of the human calcium-sensing receptor in complex with Gi and Gq proteins reveal how this receptor activates distinct G protein subtypes and how its function is modulated by a variety of ligands.
- Feng He
- , Cheng-Guo Wu
- & Georgios Skiniotis
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Conformational ensembles of the human intrinsically disordered proteome
A computational model generates conformational ensembles of 28,058 intrinsically disordered proteins and regions (IDRs) in the human proteome and sheds light on the relationship between sequence, conformational properties and functions of IDRs.
- Giulio Tesei
- , Anna Ida Trolle
- & Kresten Lindorff-Larsen
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| Open AccessThe HIV capsid mimics karyopherin engagement of FG-nucleoporins
Dissection of the nuclear pore complex provides a model in which the HIV capsid enters the nucleus through karyopherin mimicry, a mechanism likely to be conserved across other viruses.
- C. F. Dickson
- , S. Hertel
- & D. A. Jacques
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| Open AccessAlternative splicing of latrophilin-3 controls synapse formation
Latrophilin-3 organizes synapses through a convergent dual-pathway mechanism in which Gαs signalling is activated and phase-separated postsynaptic protein scaffolds are recruited.
- Shuai Wang
- , Chelsea DeLeon
- & Thomas C. Südhof
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| Open AccessDe novo design of high-affinity binders of bioactive helical peptides
A study describes a direct computational approach without experimental optimization to design high-affinity proteins that bind small helical peptides.
- Susana Vázquez Torres
- , Philip J. Y. Leung
- & David Baker
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mRNA reading frame maintenance during eukaryotic ribosome translocation
The accuracy of eukaryotic ribosome translocation relies on eukaryote-specific elements of the 80S ribosome, elongation factor 2 and transfer RNAs, all of which contribute to the maintenance of the messenger RNA reading frame.
- Nemanja Milicevic
- , Lasse Jenner
- & Gulnara Yusupova
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Ligand recognition and G-protein coupling of trace amine receptor TAAR1
TAAR1 has a rigid consensus binding motif that binds to endogenous trace amine stimuli as well as two extended binding pockets that accommodate diverse chemotypes.
- Zheng Xu
- , Lulu Guo
- & Zhenhua Shao
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| Open AccessStructure of the native myosin filament in the relaxed cardiac sarcomere
A cryo-electron tomography study reports the structure of thick myosin filaments of mouse cardiac muscle in the relaxed state in situ and the MyBP-C links that connect them with the surrounding thin actin filaments.
- Davide Tamborrini
- , Zhexin Wang
- & Stefan Raunser
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| Open AccessStructures of a sperm-specific solute carrier gated by voltage and cAMP
This study proposes a molecular mechanism of voltage activation in SLC9C1, a transporter essential for male fertility.
- Valeria Kalienkova
- , Martin F. Peter
- & Cristina Paulino
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| Open AccessTail engagement of arrestin at the glucagon receptor
Structures of the glucagon receptor bound to β-arrestin 1 are reported, providing further information about the arrestin-mediated modulation of G protein-coupled receptors.
- Kun Chen
- , Chenhui Zhang
- & Beili Wu
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| Open AccessCentral role of Tim17 in mitochondrial presequence protein translocation
Tim17 contains conserved negative charges close to the intermembrane space side of the bilayer, which are essential to initiate presequence protein translocation along a distinct transmembrane cavity of Tim17 for both classes of preproteins.
- Laura F. Fielden
- , Jakob D. Busch
- & Nils Wiedemann
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Structure of an endogenous mycobacterial MCE lipid transporter
Proteins of the Mycobacterium smegmatis Mce1 system assemble to form an elongated ABC transporter complex that is long enough to span the impermeable mycobacterial cell envelope.
- James Chen
- , Alice Fruhauf
- & Damian C. Ekiert
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| Open AccessMega-scale experimental analysis of protein folding stability in biology and design
Large-scale assays using cDNA display proteolysis are used to measure the folding stabilities of protein domains, providing a method to quantify the effects of mutations on protein folding, with applications in protein design.
- Kotaro Tsuboyama
- , Justas Dauparas
- & Gabriel J. Rocklin
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| Open AccessDe novo design of protein structure and function with RFdiffusion
Fine-tuning the RoseTTAFold structure prediction network on protein structure denoising tasks yields a generative model for protein design that achieves outstanding performance on a wide range of protein structure and function design challenges.
- Joseph L. Watson
- , David Juergens
- & David Baker
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Structural basis for the binding of DNP and purine nucleotides onto UCP1
Using cryo-electron microscopy, the structures of human UCP1 in the nucleotide-free state, the DNP activator-bound state, and the inhibitory ATP-bound state are resolved, providing details of how purine nucleotides inhibit UCP1.
- Yunlu Kang
- & Lei Chen
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Cryo-EM structure of SARS-CoV-2 postfusion spike in membrane
The SARS-CoV-2 spike internal fusion peptide forms a hairpin-like wedge that spans almost the entire lipid bilayer and the transmembrane segment wraps around the fusion peptide at the last stage of membrane fusion.
- Wei Shi
- , Yongfei Cai
- & Bing Chen
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| Open AccessA cytosolic surveillance mechanism activates the mitochondrial UPR
We identify a highly controlled cytosolic surveillance mechanism that integrates independent mitochondrial stress signals to initiate the mitochondrial unfolded protein response (UPR), revealing a link between mitochondrial and cytosolic proteostasis.
- F. X. Reymond Sutandy
- , Ines Gößner
- & Christian Münch
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| Open AccessÅngström-resolution fluorescence microscopy
The authors introduce a single-molecule DNA-barcoding method, resolution enhancement by sequential imaging, that improves the resolution of fluorescence microscopy down to the Ångström scale using off-the-shelf fluorescence microscopy hardware and reagents.
- Susanne C. M. Reinhardt
- , Luciano A. Masullo
- & Ralf Jungmann
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Structural basis of amine odorant perception by a mammal olfactory receptor
Cryo-electron microscopy structures of mouse trace amine-associated receptor 9 reveals structural motifs involved in odorant ligand recognition, including a unique disulfide bond linking the N terminus to extracellular loop 2.
- Lulu Guo
- , Jie Cheng
- & Jin-Peng Sun
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Structural basis of BAM-mediated outer membrane β-barrel protein assembly
The structural basis of the late-stage intermediate assembly of outer membrane β-barrel proteins mediated by the bacterial β-barrel assembly machinery is determined.
- Chongrong Shen
- , Shenghai Chang
- & Haohao Dong
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Noncoding translation mitigation
Combining genome-wide CRISPR screens with massively parallel analyses of human and random DNA sequences reveal a unified mechanism for the surveillance and evolution of translation products from annotated noncoding DNA.
- Jordan S. Kesner
- , Ziheng Chen
- & Xuebing Wu
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| Open AccessDe novo design of modular peptide-binding proteins by superhelical matching
A computational approach is used to design modular proteins that bind to synthetic peptides and disordered regions of human proteins with high affinity and specificity.
- Kejia Wu
- , Hua Bai
- & David Baker
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Article
| Open AccessCFTR function, pathology and pharmacology at single-molecule resolution
A structure–function analysis of cystic fibrosis transmembrane conductance regulator shows its two nucleotide-binding domains dimerize before channel opening, and reveals a mechanism through which conformational changes in the channel regulate chloride conductance.
- Jesper Levring
- , Daniel S. Terry
- & Jue Chen
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Article
| Open AccessA NPAS4–NuA4 complex couples synaptic activity to DNA repair
A neuron-specific activity-dependent DNA repair mechanism is identified, the impairment of which may lead to neurodevelopmental disorders, neurodegeneration and ageing.
- Elizabeth A. Pollina
- , Daniel T. Gilliam
- & Michael E. Greenberg
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Architecture of chloroplast TOC–TIC translocon supercomplex
A cryo-electron microscopy analysis of the Chlamydomonas reinhardtii TOC–TIC supercomplex reveals that Tic214 traverses the chloroplast inner membrane, the intermembrane space and the outer membrane, connecting the TOC complex with the TIC proteins.
- Hao Liu
- , Anjie Li
- & Zhenfeng Liu
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| Open AccessVisualization of translation and protein biogenesis at the ER membrane
Structural studies of the ribosome-associated endoplasmic reticulum translocon complex based on cryo-electron tomography and molecular modelling reveal multiple intermediate states and interactions between the components of the complex and its cofactors.
- Max Gemmer
- , Marten L. Chaillet
- & Friedrich Förster
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Article
| Open AccessStructural basis of tankyrase activation by polymerization
Structural insights into the poly-ADP-ribosyltransferase tankyrase reveal its filamentous architecture and illustrate how assembly controls catalytic and non-catalytic functions.
- Nisha Pillay
- , Laura Mariotti
- & Sebastian Guettler
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| Open AccessStructural basis of actin filament assembly and aging
Cryo-electron microscopy structures of skeletal F-actin show solvent-driven rearrangements governing actin filament assembly and aging with potential application in design of drugs and small molecules for imaging and therapy.
- Wout Oosterheert
- , Björn U. Klink
- & Stefan Raunser
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Recognition of cyclic dinucleotides and folates by human SLC19A1
Two cyclic dinucleotide molecules bind within the cavity of human SLC19A1 as a compact dual-molecule unit, whereas folate and antifolate bind to SLC19A1 as a monomer and occupy a distinct pocket of the cavity.
- Qixiang Zhang
- , Xuyuan Zhang
- & Pu Gao
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Structure of dynein–dynactin on microtubules shows tandem adaptor binding
The structure of the complete dynein–dynactin complex and its interaction with microtubules and cargo adaptors are visualized using cryo-electron microscopy.
- Sami Chaaban
- & Andrew P. Carter
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Article
| Open AccessStructural insights into auxin recognition and efflux by Arabidopsis PIN1
Structures of the Arabidopsis thaliana auxin exporter PIN1 in the apo state, bound to the natural auxin or bound to an inhibitor provide insights into the polar auxin transport mechanisms mediated by PIN family transporters.
- Zhisen Yang
- , Jing Xia
- & Linfeng Sun
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Sestrin mediates detection of and adaptation to low-leucine diets in Drosophila
Fruitflies require Sestrin to regulate mTORC1 signalling in response to dietary leucine, survive a diet low in leucine, and control leucine-sensitive physiological characteristics, which establishes Sestrin as a physiologically relevant leucine sensor.
- Xin Gu
- , Patrick Jouandin
- & David M. Sabatini
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| Open AccessCryo-EM structure of an active bacterial TIR–STING filament complex
Through structural analysis of the activation of bacterial STING, the molecular basis of STING filament formation and TIR effector domain activation in antiphage signalling is defined.
- Benjamin R. Morehouse
- , Matthew C. J. Yip
- & Philip J. Kranzusch
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Mechanisms and inhibition of Porcupine-mediated Wnt acylation
Cryo-electron microscopy structures of human Porcupine in complex with palmitoleoyl-coenzyme A, the inhibitor LGK974 and its peptide substrate suggest a mechanism for Wnt acylation.
- Yang Liu
- , Xiaofeng Qi
- & Xiaochun Li
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Structure of Tetrahymena telomerase-bound CST with polymerase α-primase
Cryo-electron microscopy structures of Tetrahymena thermophila telomerase-bound Ctc1–Stn1–Ten1 and DNA polymerase α–primase provide insights into the molecular mechanisms underlying telomere replication and maintenance.
- Yao He
- , He Song
- & Juli Feigon
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Structural basis of GABA reuptake inhibition
Structural determination of GAT1 using cryo-electron microscopy provides insights into the biology and pharmacology of this GABA transporter.
- Zenia Motiwala
- , Nanda Gowtham Aduri
- & Cornelius Gati
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Tethered peptide activation mechanism of the adhesion GPCRs ADGRG2 and ADGRG4
Cryo-electron microscopy structures of three adhesion G protein-coupled receptors (aGPCRs) complexes provide insight into the tethered activation mechanism of aGPCRs and show the potential for rational design of agonists.
- Peng Xiao
- , Shengchao Guo
- & Xiao Yu
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Structural basis for the tethered peptide activation of adhesion GPCRs
Adhesion GPCRs involved in cell and matrix interactions signal through a distinct self-cleavage, self-activation mechanism.
- Yu-Qi Ping
- , Peng Xiao
- & Jin-Peng Sun
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Structure of active human telomerase with telomere shelterin protein TPP1
Cryo-electron microscopy structures of human telomerase and telomerase in complex with TPP1 provide insights into the interactions of these proteins and their activities.
- Baocheng Liu
- , Yao He
- & Juli Feigon
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| Open AccessStructural basis of tethered agonism of the adhesion GPCRs ADGRD1 and ADGRF1
Cryo-electron microscopy structures of the adhesion G protein-coupled receptors ADGRD1 and ADGRF1 provide insight into how these receptors are activated in an intrinsic manner through a ‘stalk’ region that acts as a tethered agonist.
- Xiangli Qu
- , Na Qiu
- & Beili Wu
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Structural basis of lipopolysaccharide maturation by the O-antigen ligase
Cryo-electron microscopy structures of the bacterial O-antigen ligase WaaL, combined with genetics, biochemistry and molecular dynamics simulations, provide insight into the mechanism by which WaaL catalyses the biosynthesis of lipopolysaccharide.
- Khuram U. Ashraf
- , Rie Nygaard
- & Filippo Mancia
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| Open AccessActivation mechanism of the class D fungal GPCR dimer Ste2
Cryo-electron microscopy structures of ligand-free, agonist-bound and antagonist-bound Ste2 show that this class D1 G protein-coupled receptor has a distinct mechanism of activation compared with other receptor classes.
- Vaithish Velazhahan
- , Ning Ma
- & Christopher G. Tate
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