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| Open AccessStructure of the human Bre1 complex bound to the nucleosome
The structure of the nucleosome-bound human Bre1 complex reveals that its two RING domains bind the acidic patch and nucleosomal DNA, directing the E2 enzyme and ubiquitin for H2BK120-specific ubiquitination. The binding mode suggests a possible regulatory mechanism through nucleosomal DNA flexibility.
- Shuhei Onishi
- , Kotone Uchiyama
- & Toru Sengoku
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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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| Open AccessAn OLD protein teaches us new tricks: prokaryotic antiviral defense
Reporting in Nature Communications, Huo and colleagues provide three-dimensional structures of a bacterial immune defense system called Gabija. This work builds on recently published structural and functional studies and contributes strong evidence that protein assembly formation is essential for antiviral function.
- Eirene Marie Q. Ednacot
- & Benjamin R. Morehouse
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Article
| Open AccessA structure-based designed small molecule depletes hRpn13Pru and a select group of KEN box proteins
Here, the authors identify a small molecule degrader (XL44) for hRpn13 and solve the XL44-hRpn13 structure. XL44 induces apoptosis in myeloma cells with hRpn13 dependency and also targets KEN box proteins PCLAF and RRM2. Loss of hRpn13 and PCLAF abrogates XL44 restriction of cell viability.
- Xiuxiu Lu
- , Monika Chandravanshi
- & Kylie J. Walters
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Article
| Open AccessThe evolutionary origin of naturally occurring intermolecular Diels-Alderases from Morus alba
Diels-Alderases (DAs), enzymes catalyzing [4 + 2] cycloaddition reactions, are of high interest, but insights into their evolution are lacking. Here, the authors investigate the evolutionary origins of the intermolecular DAs in the biosynthesis of Moraceae plant-derived Diels-Alder-type secondary metabolites, suggesting they evolved from an ancestor functioning as a flavin adenine dinucleotide-dependent oxidocyclase.
- Qi Ding
- , Nianxin Guo
- & Xiaoguang Lei
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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 AccessStructure of an open KATP channel reveals tandem PIP2 binding sites mediating the Kir6.2 and SUR1 regulatory interface
KATP channels regulate insulin secretion and are activated by PIP2. Here, the authors show PIP2 binds between SUR1 and Kir6.2 to open the channel, and a neonatal diabetes mutation stabilizes KATP channels in a PIP2-bound open conformation.
- Camden M. Driggers
- , Yi-Ying Kuo
- & Show-Ling Shyng
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Article
| Open AccessLegionella metaeffector MavL reverses ubiquitin ADP-ribosylation via a conserved arginine-specific macrodomain
The pathogen Legionella pneumophila mediates NAD+-dependent ubiquitination pathways upon infection. Here, the authors show the Legionella effector MavL reverses ubiquitin ADP-ribosylation to regulate these pathways. MavL represents a new macrodomain class specific for reversal of arginine ADP-ribosylation with distinct ADP-ribose binding features.
- Zhengrui Zhang
- , Jiaqi Fu
- & Chittaranjan Das
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Article
| Open AccessTwo DOT1 enzymes cooperatively mediate efficient ubiquitin-independent histone H3 lysine 76 tri-methylation in kinetoplastids
Trypanosoma brucei DOT1A and DOT1B methylate H3K76 without H2B-ubiquitin. Based on structural and enzymatic data, Frisbie et al. reveal a mechanism of how these enzymes cooperatively and efficiently tri-methylate H3K76 in a ubiquitin-independent way.
- Victoria S. Frisbie
- , Hideharu Hashimoto
- & Erik W. Debler
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Article
| Open AccessThe SecM arrest peptide traps a pre-peptide bond formation state of the ribosome
Stalling of ribosomes by the nascent polypeptide chain is widely used to regulate gene expression. Here, Gersteuer et al determine cryo-EM structures of SecM-stalled ribosomes revealing the mechanism by which the SecM peptide arrests translation.
- Felix Gersteuer
- , Martino Morici
- & Daniel N. Wilson
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Article
| Open AccessRAPP-containing arrest peptides induce translational stalling by short circuiting the ribosomal peptidyltransferase activity
Translation of RAPP (Arg-AlaPro-Pro) motifs induces ribosome stalling. Here, structures of RAPP-stalled ribosomes reveal that RAPP motifs short circuit the ribosomal peptidyltransferase activity to induce stalling.
- Martino Morici
- , Sara Gabrielli
- & Daniel N. Wilson
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Article
| Open AccessStructure of orthoreovirus RNA chaperone σNS, a component of viral replication factories
Orthoreovirus σNS, essential for forming viral replication factories, has RNA chaperone activity that requires the association of σNS dimers into filamentous structures stabilized by domain-swapping interactions of the flexible N-terminal arms.
- Boyang Zhao
- , Liya Hu
- & B. V. Venkataram Prasad
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| Open AccessCryo-EM structures of type IV pili complexed with nanobodies reveal immune escape mechanisms
Bacterial type IV pili are filamentous cell surface structures and candidate targets for vaccine development. Here, authors determine how antibodies interact with pili at the structural level providing insight into immune escape mechanisms and potential countermeasures.
- David Fernandez-Martinez
- , Youxin Kong
- & Guillaume Duménil
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Article
| Open AccessStructural and mechanistic insights into activation of the human RNA ligase RTCB by Archease
RTCB-type RNA ligases play important roles in tRNA splicing, the unfolded protein response and RNA repair. Here, Gerber et al. present structural snapshots of RTCB’s reaction cycle, and show how an activation complex with Archease primes RTCB for ligation.
- Janina Lara Gerber
- , Suria Itzel Morales Guzmán
- & Jirka Peschek
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Article
| Open AccessStructural basis for autoinhibition by the dephosphorylated regulatory domain of Ycf1
Yeast cadmium factor 1 (Ycf1), a heavy metal and glutathione transporter, is regulated by an intrinsically disordered region called the regulatory domain. In this work, the authors show that this domain controls activity through autoinhibition of the glutathione cavity when it is dephosphorylated.
- Nitesh Kumar Khandelwal
- & Thomas M. Tomasiak
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Article
| Open AccessArchitecture of symbiotic dinoflagellate photosystem I–light-harvesting supercomplex in Symbiodinium
Here the authors determine the cryoEM structure of Symbiodinium photosystem I, revealing a distinct architecture and pigment network of this light-harvesting supercomplex.
- Long-Sheng Zhao
- , Ning Wang
- & Yu-Zhong Zhang
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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 AccessComplexes of tubulin oligomers and tau form a viscoelastic intervening network cross-bridging microtubules into bundles
X-ray scattering and electron microscopy are used in concert to show that complexes of tubulin oligomers and tau are building blocks of an intervening network that cross-bridge microtubules into bundles with the same linear geometry observed in neurons.
- Phillip A. Kohl
- , Chaeyeon Song
- & Cyrus R. Safinya
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Article
| Open AccessDual receptor-sites reveal the structural basis for hyperactivation of sodium channels by poison-dart toxin batrachotoxin
The poison dart toxin batrachotoxin is the most lethal voltage-gated sodium channel toxin. Here authors identify the toxin bound specifically at two homologous receptor sites, which cause channel hyperactivation by positively modulating channel gating and altering ion conductance.
- Lige Tonggu
- , Goragot Wisedchaisri
- & William A. Catterall
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Article
| Open AccessHigh-resolution cryo-EM of the human CDK-activating kinase for structure-based drug design
Discovery of new therapeutics has been hampered by the often-limiting resolution and throughput of cryo-EM. Here, the authors determine high-resolution cryo-EM structures of the CDK-activating kinase to establish a methodological framework for the use of cryo-EM in structure-based drug design.
- Victoria I. Cushing
- , Adrian F. Koh
- & Basil J. Greber
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| Open AccessCryo-EM structures of Banna virus in multiple states reveal stepwise detachment of viral spikes
Here, Li et al. provide the cryo-EM structures of Banna virus (BAV) in four configurations. VP10 functions as a unique cementing protein to stabilize the capsid shells and spikes in the full particles and during cell entry. Structural transition from BAV virions to cores is a stepwise process of dissociation of receptor binding protein VP9 and membrane penetration protein VP4.
- Zhiqiang Li
- , Han Xia
- & Sheng Cao
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| 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 AccessSubstrate recognition mechanism of the endoplasmic reticulum-associated ubiquitin ligase Doa10
Doa10/MARCHF6 is a conserved E3 ubiquitin ligase in the endoplasmic reticulum (ER) membrane in eukaryotes, but its molecular mechanism was unknown. The authors combine cryo-EM, computational and biochemical analyses to reveal how Doa10 recognizes its substrate proteins for ER-associated degradation.
- Kevin Wu
- , Samuel Itskanov
- & Eunyong Park
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Article
| Open AccessStructural basis for self-discrimination by neoantigen-specific TCRs
Neoantigen-specific T cells recognise neoantigen-MHC complexes on target tumour cells. Here, the authors describe a molecular mechanism by which the neoantigen Hsf2 p.K72N is recognised by a corresponding high affinity Hsf2 p.K72N-reactive T cell receptor, 47BE7, from the mouse melanoma line B16F10.
- John P. Finnigan
- , Jenna H. Newman
- & Nina Bhardwaj
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| Open AccessA three-level regulatory mechanism of the aldo-keto reductase subfamily AKR12D
Here, the authors characterise an aldo-keto reductase AKRtyl, which belongs to a previously unidentified subfamily AKR12D. They uncover a complex mechanism of allosteric regulation that is mediated by 3 distinct states.
- Zhihong Xiao
- , Jinyin Zha
- & Shaobo Dai
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Article
| Open AccessDeepETPicker: Fast and accurate 3D particle picking for cryo-electron tomography using weakly supervised deep learning
Picking particles of biological macromolecules is critical for solving their structures in situ using cryo-electron tomograms. Here, authors develop DeepETPicker, a deep learning-based tool for fast, accurate, and automated picking of three-dimensional particles.
- Guole Liu
- , Tongxin Niu
- & Ge Yang
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Article
| Open AccessStructural insights into IL-11-mediated signalling and human IL6ST variant-associated immunodeficiency
IL-11 and IL-6 signal by binding gp130. Here, Gardner et al. use cryoEM to discover how IL-11 engages gp130 and co-receptor IL-11Rα. Together with MD simulations, they provide insight into gp130 mutations that cause human immunodeficiencies.
- Scott Gardner
- , Yibo Jin
- & Doryen Bubeck
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Article
| Open AccessDimerization-dependent serine protease activity of FAM111A prevents replication fork stalling at topoisomerase 1 cleavage complexes
FAM111A is a serine protease important for DNA replication and antiviral defense. Here, the authors report that the FAM111A dimerization is crucial for its proteolytic activity and for promoting DNA replication at trapped topoisomerase I.
- Sowmiya Palani
- , Yuka Machida
- & Yuichi J. Machida
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Article
| Open AccessChloride intracellular channel (CLIC) proteins function as fusogens
The Chloride Intracellular Channel (CLIC) protein family is highly conserved, yet their function remains a matter of ongoing research. Here, authors reveal their ability to facilitate membrane fusion, shedding light on their physiological role.
- Bar Manori
- , Alisa Vaknin
- & Yoni Haitin
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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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| Open AccessIn-cell NMR suggests that DNA i-motif levels are strongly depleted in living human cells
I-Motifs (iM) are non-canonical DNA structures potentially forming in the accessible, single stranded, cytosine-rich genomic region, but the specific contributions of several factors involved in their formation are unknown. Using in-cell NMR, the authors examined DNA i-motif formation in human cells at body temperature, suggesting i-M occur in a small portion (<1%) of genomic sites predisposed to its formation.
- Pavlína Víšková
- , Eva Ištvánková
- & Lukáš Trantírek
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Article
| Open AccessMolecular basis of TMPRSS2 recognition by Paeniclostridium sordellii hemorrhagic toxin
Paeniclostridium sordellii hemorrhagic toxin (TcsH) targets TMPRSS2 to enter the host cells. Here, authors showed the cryo-EM structures of the TcsH-TMPRSS2 complex, providing a toxin-receptor interaction model for large clostridial toxins.
- Ruoyu Zhou
- , Liuqing He
- & Liang Tao
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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 AccessFilament formation drives catalysis by glutaminase enzymes important in cancer progression
Mitochondrial enzymes, collectively known as glutaminase, satisfy the metabolic requirements of cancer cells. Here the authors show that glutaminases form filamentous structures necessary for their catalytic activity.
- Shi Feng
- , Cody Aplin
- & Richard A. Cerione
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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 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 AccessStructural insight into an Arl1–ArfGEF complex involved in Golgi recruitment of a GRIP-domain golgin
Arl1 is a GTP-binding protein that interacts with the guanine nucleotide exchange factor Gea2 to recruit the golgin Imh1 to the Golgi. Here, the authors report structures of the full-length Gea2 and the Arl1–Gea2 complex, with insights into the mechanism of their function in membrane trafficking.
- H. Diessel Duan
- , Bhawik K. Jain
- & Huilin Li
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Article
| Open AccessAlternative low-populated conformations prompt phase transitions in polyalanine repeat expansions
Here, the authors show that pathogenic mutations in the polyalanine expansions of PHOX2B promote nascent structural conformations that trigger irreversible phase transitions that arrest wild-type PHOX2B, disrupting function.
- Rosa Antón
- , Miguel Á. Treviño
- & Javier Oroz
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Article
| Open AccessAltered receptor binding, antibody evasion and retention of T cell recognition by the SARS-CoV-2 XBB.1.5 spike protein
New variants of SARS-CoV-2 virus can evolve such that antibodies that recognised previous versions are not able to recognise newer versions. Here the authors characterise antibody binding to the XBB.1.5 variant and how antibodies and T cells from persons infected with earlier versions of SARS-CoV-2 are able to recognise and/or bind to the XBB.1.5 spike protein.
- Dhiraj Mannar
- , James W. Saville
- & Sriram Subramaniam
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Article
| Open AccessToxoplasma gondii actin filaments are tuned for rapid disassembly and turnover
Actin is critical to the survival of the parasite Toxoplasma gondii. In this study, Hvorecny and Sladewski et al. show that T. gondii actin forms intrinsically dynamic filaments in vitro due to differences in assembly contacts in the D-loop.
- Kelli L. Hvorecny
- , Thomas E. Sladewski
- & Aoife T. Heaslip
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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 AccessFunctional regulation of aquaporin dynamics by lipid bilayer composition
Membrane proteins depend on their lipid environments. Using aquaporin as a model, the authors show that the choice of lipid bilayer fundamentally affects membrane protein structure, thermodynamics, kinetic, and function, even to the point of lipid-based inhibition.
- Anh T. P. Nguyen
- , Austin T. Weigle
- & Diwakar Shukla
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Article
| Open AccessAn anti-CRISPR that represses its own transcription while blocking Cas9-target DNA binding
Anti-CRISPR proteins can help to evade bacterial immunity. Here, the authors elucidate the mechanism of AcrIIA15, which inhibits CRISPR-Cas9 system and also functions as a transcriptional repressor of itself as a fusion protein.
- Xieshuting Deng
- , Wei Sun
- & Yanli Wang
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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 AccessStructure-function analysis of the cyclic β-1,2-glucan synthase from Agrobacterium tumefaciens
Here, the authors present the structure of cyclic β-1,2-glucan synthase from Agrobacterium tumefaciens, revealing a distinct mechanism that uses a tyrosine-linked oligosaccharide intermediate in cycles of polymerization and processing of the glucan chain.
- Jaroslaw Sedzicki
- , Dongchun Ni
- & Christoph Dehio
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Article
| Open AccessTopBP1 utilises a bipartite GINS binding mode to support genome replication
Effective and regulated activation of the Mcm2-7 helicase underlies faithful genome replication. Here the authors reveal mechanistic detail how the pre-loading complex proteins TopBP1 and GINS interact and, thus, how the helicase activator GINS loads on Mcm2-7 during replication origin firing.
- Matthew Day
- , Bilal Tetik
- & Dominik Boos