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| Open AccessDefining molecular glues with a dual-nanobody cannabidiol sensor
Molecular glue has been used as a broad term describing a class of protein interaction-promoting compounds. Here, the authors outline two unifying thermodynamic features to formally define molecular glues and guide their prospective discovery.
- Shiyun Cao
- , Shoukai Kang
- & Ning Zheng
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Article
| Open AccessStructural and biochemical rationale for enhanced spike protein fitness in delta and kappa SARS-CoV-2 variants
Saville, Mannar et al. provide a structural basis for enhanced antibody evasion and ACE2 binding by the Delta SARS-CoV-2 spike protein. They further identify a head-to-head dimer-of-trimers cryoEM reconstruction unique to the Kappa variant spike.
- James W. Saville
- , Dhiraj Mannar
- & Sriram Subramaniam
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Article
| Open AccessMechanisms underlying TARP modulation of the GluA1/2-γ8 AMPA receptor
AMPA glutamate receptors, mediate the majority of excitatory signaling in the brain. Here the authors show how the auxiliary subunit TARP-γ8 shapes gating kinetics, ion conductance and rectification properties of the heteromeric GluA1/2 AMPA receptor.
- Beatriz Herguedas
- , Bianka K. Kohegyi
- & Ingo H. Greger
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Article
| Open AccessDifferential activation mechanisms of lipid GPCRs by lysophosphatidic acid and sphingosine 1-phosphate
Liu et al. report structures of human sphingosine 1-phosphate (S1P) receptor 1 (S1P1) in complex with Gi and S1P or the multiple sclerosis (MS) drug Siponimod, as well as human lysophosphatidic acid (LPA) receptor 1 (LPA1) in complex with Gi and LPA, revealing distinct conformations of the lysophospholipids interacting with their cognate GPCRs.
- Shian Liu
- , Navid Paknejad
- & Xin-Yun Huang
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Article
| Open AccessNeutralizing antibodies induced in immunized macaques recognize the CD4-binding site on an occluded-open HIV-1 envelope trimer
Neutralizing antibodies (bNAbs) against HIV-1 are exclusively directed against the viral envelope protein (Env) and mainly target Env in a closed, prefusion state. Here, Yang et al. structurally characterize two heterologously-neutralizing CD4-binding site (CD4bs) antibodies isolated from sequentially immunized macaques, and show that these antibodies recognize the CD4bs on Env trimers in an „occluded-open‟ conformation between closed, as targeted by bNAbs, and fully-open, as recognized by CD4.
- Zhi Yang
- , Kim-Marie A. Dam
- & Pamela J. Bjorkman
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Article
| Open AccessTousled-like kinase 2 targets ASF1 histone chaperones through client mimicry
Tousled-like kinase 2 (TLK2) phosphorylates ASF1 histone chaperones to promote nucleosome assembly in S phase. Here, the authors show that TLK2 targets ASF1 by simulating its client protein histone H3, exploiting a primordial protein interaction surface for regulatory control.
- Bertrand Simon
- , Hua Jane Lou
- & David A. Calderwood
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Article
| Open AccessCryo-EM structures of human bradykinin receptor-Gq proteins complexes
Type 2 bradykinin receptor (B2R) is essential in vasodilation and cardioprotection. Here the authors present two cryo-EM structures of human B2R-Gq in complex with bradykinin and kallidin to elucidate the mechanisms for ligand binding, receptor activation, and Gq proteins coupling.
- Jinkang Shen
- , Dongqi Zhang
- & Haitao Zhang
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Article
| Open AccessAn archaellum filament composed of two alternating subunits
The archaellum is a molecular machine used by archaea to swim, consisting of an intracellular motor that drives the rotation of an extracellular filament composed of multiple copies of proteins named archaellins. Here, the authors use electron cryo-microscopy to elucidate the structure of an archaellum, and find that the filament is composed of two alternating archaellins.
- Lavinia Gambelli
- , Michail N. Isupov
- & Bertram Daum
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Article
| Open AccessInduction of tier-2 neutralizing antibodies in mice with a DNA-encoded HIV envelope native like trimer
HIV envelope is a target for vaccine development, but induction of broadly neutralizing antibodies has been difficult. Here, the authors show that electroporation with a synthetic DNA vaccine construct allows in vivo production of HIV envelope native like trimers to induce autologous tier-2 neutralizing antibodies targeting a C3/V5 epitope in mice.
- Ziyang Xu
- , Susanne Walker
- & Daniel W. Kulp
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Article
| Open AccessMolecular mechanism of Arp2/3 complex inhibition by Arpin
The Arp2/3 complex inhibitor Arpin controls cell migration by interrupting a feedback loop involving Rac-WAVE-Arp2/3 complex Here, the authors use structural, biochemical, and cellular studies to reveal Arpin’s mechanism of inhibition.
- Fred E. Fregoso
- , Trevor van Eeuwen
- & Roberto Dominguez
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Article
| Open AccessGut microbiome of the largest living rodent harbors unprecedented enzymatic systems to degrade plant polysaccharides
Here, Cabral et al., perform a multi-omics analysis of the gut microbiome of capybara, the largest living rodent, unveiling enzymatic mechanisms for the breakdown of lignocellulosic biomass, and report two undescribed families of carbohydrate-active enzymes.
- Lucelia Cabral
- , Gabriela F. Persinoti
- & Mario T. Murakami
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Article
| Open AccessA dual mechanism of action of AT-527 against SARS-CoV-2 polymerase
The drug AT-527 targets the SARS-CoV-2 replication machinery. Here the authors use Cryo-EM to show how AT-527 inhibits SARS-CoV-2 polymerase by acting as an immediate RNA chain terminator and stably binding in a NiRAN active-site pocket; impeding an essential nucleotide-transfer activity.
- Ashleigh Shannon
- , Véronique Fattorini
- & Bruno Canard
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Article
| Open AccessPplD is a de-N-acetylase of the cell wall linkage unit of streptococcal rhamnopolysaccharides
The cell wall of the bacterial pathogen Group A Streptococcus is decorated with a polysaccharide termed GAC, which is a target for vaccine development. Here, Rush et al. characterize the linkage between GAC and peptidoglycan, and identify a protein that deacetylates the linkage and thus protects the pathogen against host cationic antimicrobial proteins.
- Jeffrey S. Rush
- , Prakash Parajuli
- & Natalia Korotkova
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Article
| Open AccessAdaptation to genome decay in the structure of the smallest eukaryotic ribosome
Many parasitic organisms contain molecular structures that are drastically smaller than analogous structures in non-parasitic organisms. Here the authors describe a cryo-EM structure of the ribosome from E. cuniculi that reveals that it compensated rRNA truncations by evolving the ability to use small molecules as ribosomal building blocks.
- David Nicholson
- , Marco Salamina
- & Sergey V. Melnikov
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Article
| Open AccessCatalytic trajectory of a dimeric nonribosomal peptide synthetase subunit with an inserted epimerase domain
The catalytic domains in nonribosomal peptide synthetases (NRPSs) are responsible for a choreography of events that elongates substrates into natural products. Here, the authors present cryo-EM structures of a siderophore-producing dimeric NRPS elongation module in multiple distinct conformations, which provides insight into the mechanisms of catalytic trajectory.
- Jialiang Wang
- , Dandan Li
- & Zhijun Wang
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Article
| Open AccessHost receptor-targeted therapeutic approach to counter pathogenic New World mammarenavirus infections
Five New World mammarenaviruses (NWMs) enter cells via binding to human transferrin receptor 1 (hTfR1). Here, Hickerson et al. show that hTfR1 targeting antibodies partially protect hTfR1-transgenic mice from lethal NWM challenge via competition of anti-hTfR1 antibody and viral glycoprotein for hTfR1.
- Brady T. Hickerson
- , Tracy R. Daniels-Wells
- & Brian B. Gowen
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Article
| Open AccessStructure of Vibrio collagenase VhaC provides insight into the mechanism of bacterial collagenolysis
The collagenolytic mechanism of Vibrio collagenase, a virulence factor, remains unclear. Here, the authors report the structure of Vibrio collagenase VhaC and propose the mechanism for collagen recognition and degradation, providing new insight into bacterial collagenolysis.
- Yan Wang
- , Peng Wang
- & Yu-Zhong Zhang
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Article
| Open AccessStructures and function of a tailoring oxidase in complex with a nonribosomal peptide synthetase module
Nonribosomal peptide synthetases work with additional enzymes to synthesise secondary metabolites and therapeutics. Here, the authors explore bacillamide D synthesis and show the oxidase action is done while the intermediate is attached to the synthetase and replicate this with an oxidase bound synthetase for bioengineering applications.
- Camille Marie Fortinez
- , Kristjan Bloudoff
- & T. Martin Schmeing
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Article
| Open AccessMultiple conformations of trimeric spikes visualized on a non-enveloped virus
Zhang and Cui et al. present in situ cryoEM structures of the trimeric spike of cytoplasmic polyhedrosis virus in both open and close conformations, and demonstrate that spike detachment from the capsid is triggered by the presence of SAM and ATP.
- Yinong Zhang
- , Yanxiang Cui
- & Z. Hong Zhou
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Article
| Open AccessStructural basis for safe and efficient energy conversion in a respiratory supercomplex
Aerobic energy metabolism is driven by proton-pumping respiratory supercomplexes. The study reports the structural basis for energy conversion in such supercomplex. It may aid metabolic engineering and drug design against diphtheria and tuberculosis.
- Wei-Chun Kao
- , Claire Ortmann de Percin Northumberland
- & Carola Hunte
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Article
| Open AccessCarbohydrate-aromatic interface and molecular architecture of lignocellulose
The plant biomass is a composite formed by a variety of polysaccharides and an aromatic polymer named lignin. Here, the authors use solid-state NMR spectroscopy to unveil the carbohydrate-aromatic interface that leads to the variable architecture of lignocellulose biomaterials.
- Alex Kirui
- , Wancheng Zhao
- & Tuo Wang
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Article
| Open AccessThe MuvB complex binds and stabilizes nucleosomes downstream of the transcription start site of cell-cycle dependent genes
The MuvB protein complex regulates genes that are differentially expressed through the cell cycle, yet its precise molecular function has remained unclear. Here the authors reveal MuvB associates with the nucleosome adjacent to the transcription start site of cell-cycle genes and that the tight positioning of this nucleosome correlates with MuvB-dependent gene repression.
- Anushweta Asthana
- , Parameshwaran Ramanan
- & Seth M. Rubin
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Article
| Open AccessHigh-resolution structures of a thermophilic eukaryotic 80S ribosome reveal atomistic details of translocation
High-resolution cryo-EM structures of a thermophilic 80S ribosome in two rotational states in complex with the protective factor Stm1, eEF2, and nascent chains are presented, providing insights into rRNA modifications and eukaryotic translation.
- Miglė Kišonaitė
- , Klemens Wild
- & Irmgard Sinning
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Article
| Open AccessIon currents through Kir potassium channels are gated by anionic lipids
The Kir potassium channels are known to operate and gate without a major conformational change. Here, the authors identify the permeation gate of Kir channels as a steric plug within the conduction pathway, describing how tightly associated anionic lipids pushing into fenestrations in the pore walls engage with the plug to operate the gate.
- Ruitao Jin
- , Sitong He
- & Jacqueline M. Gulbis
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Article
| Open AccessA non-catalytic herpesviral protein reconfigures ERK-RSK signaling by targeting kinase docking systems in the host
The herpesvirus protein ORF45 can bind the two host kinases ERK and RSK but how this affects cell signalling is unclear. Here, the authors show that ORF45 hijacks the ERK-RSK complex by binding to the two kinases with optimized linear motifs and interfering with the host kinase docking systems.
- Anita Alexa
- , Péter Sok
- & Attila Reményi
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Article
| Open AccessModular assembly of the principal microtubule nucleator γ-TuRC
The human microtubule nucleator γ-TuRC is composed of more than thirty subunits, including actin. Here the authors reveal the structural mechanism of modular γ-TuRC assembly and show a functional role of actin in microtubule nucleation.
- Martin Würtz
- , Erik Zupa
- & Stefan Pfeffer
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Article
| Open AccessStructural insights into the BRAF monomer-to-dimer transition mediated by RAS binding
RAF kinases are essential for RAS protein signalling but how RAS binding regulates dimerization and activation of RAF has remained unclear. Here, the authors report cryoEM structures that provide mechanistic insights into the RAS-mediated monomer-to-dimer transition of full-length BRAF.
- Juliana A. Martinez Fiesco
- , David E. Durrant
- & Ping Zhang
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Article
| Open AccessStructural basis of the ligand binding and signaling mechanism of melatonin receptors
Melatonin receptors (MT1 and MT2) are the targets for melatonin, the major neurohormone involved in circadian rhythm and sleep regulation. Here the authors describe the structures of 2-iodomelatonin and ramelteon bound MT1–Gi and MT2-Gi, revealing that MT1 and MT2 possess distinctive features within the ligand-binding pocket.
- Qinggong Wang
- , Qiuyuan Lu
- & Yuyong Tao
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Article
| Open AccessInterplay between an ATP-binding cassette F protein and the ribosome from Mycobacterium tuberculosis
The authors present structures of the MtbEttA protein bound to or free of the ribosome from Mycobacterium tuberculosis under different nucleotide states, which provide insights into the mechanism of translational regulation by EttA-like proteins.
- Zhicheng Cui
- , Xiaojun Li
- & Junjie Zhang
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Article
| Open AccessA structural basis for the diverse linkage specificities within the ZUFSP deubiquitinase family
ZUFSP-type enzymes cleave ubiquitin chains in a linkage-specific fashion, but members from different organisms have different specificities. Using an inter-kingdom comparison of activities and structures, the authors identify the domains responsible for this discrepancy.
- Thomas Hermanns
- , Christian Pichlo
- & Kay Hofmann
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Article
| Open AccessStructure of a type IV secretion system core complex encoded by multi-drug resistance F plasmids
Bacteria conjugatively transfer DNA through type IV secretion systems (T4SSs). Here, the authors report the structure of a T4SS outer-membrane core complex (OMCC), revealing how a distinct C13:C17 symmetry mismatch exhibited by peripheral ring and central cone substructures is accommodated.
- Xiangan Liu
- , Pratick Khara
- & Bo Hu
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Article
| Open AccessCrystal structure of the α1B-adrenergic receptor reveals molecular determinants of selective ligand recognition
This study reports the X-ray structure of the α1B-adrenergic G protein-coupled receptor bound to an inverse agonist, and unveils key determinants of subtype-selective ligand binding that may help the design of aminergic drugs with fewer side-effects.
- Mattia Deluigi
- , Lena Morstein
- & Andreas Plückthun
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Article
| Open AccessIdentification of a diarylpentanoid-producing polyketide synthase revealing an unusual biosynthetic pathway of 2-(2-phenylethyl)chromones in agarwood
2-(2-Phenylethyl)chromones (PECs) contribute to the distinctive fragrance of agarwood. Here the authors identify a diarylpentanoid-producing polyketide synthase from Aquilaria sinensis and show how it catalyzes PEC formation.
- Xiao-Hui Wang
- , Bo-Wen Gao
- & She-Po Shi
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Article
| Open AccessStructure and function of a family of tick-derived complement inhibitors targeting properdin
Properdin is the only known positive regulator of the human complement system, stabilising the convertase C3 in the alternative pathway of complement activation. Here, the authors report the identification and characterisation of a species-specific properdin inhibitor CirpA, derived from tick saliva.
- Katharina Braunger
- , Jiyoon Ahn
- & Susan M. Lea
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Article
| Open AccessMolecular mechanism of agonism and inverse agonism in ghrelin receptor
Ghrelin receptor regulates energy homeostasis through constitutive activity or by the ghrelin. Here the authors report two structures of ghrelin receptor bound to agonist and inverse agonist, providing insights into the mechanism of inverse agonism, which is of interest for specific ligand design.
- Jiao Qin
- , Ye Cai
- & Zhenhua Shao
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Article
| Open AccessSingle particle cryo-EM structure of the outer hair cell motor protein prestin
Prestin, expressed in outer hair cell (OHC), belongs to the Slc26 transporter family and functions as a voltage-driven motor that drives OHC electromotility. Here, the authors report cryo-EM structure and characterization of gerbil prestin, with insights into its mechanism of action.
- Carmen Butan
- , Qiang Song
- & Joseph Santos-Sacchi
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Article
| Open AccessStructural basis of prokaryotic ubiquitin-like protein engagement and translocation by the mycobacterial Mpa-proteasome complex
Pup is the bacterial analog of ubiquitin for targeting proteins to the proteasome. Here, the authors use cryoEM to visualize structures of the Mycobacterium tuberculosis proteasome translocating a Pup-tagged substrate.
- Mikhail Kavalchuk
- , Ahmad Jomaa
- & Eilika Weber-Ban
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Article
| Open AccessStructural insights in cell-type specific evolution of intra-host diversity by SARS-CoV-2
BriSΔ, a SARS-CoV-2 variant from clinical isolate hCoV/England/02/2020, comprises a deletion in a spike cleavage site. The structure and molecular dynamics of this spike provides mechanistic insights into how the deletion modulates virus infectivity.
- Kapil Gupta
- , Christine Toelzer
- & Imre Berger
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Article
| Open AccessMapping inhibitory sites on the RNA polymerase of the 1918 pandemic influenza virus using nanobodies
Influenza viruses carry their own RNAdependent RNA-polymerase that is highly conserved and a promising anti-viral target. Combining functional and structural data, Keown et al. characterise the inhibitory effect of nanobodies on 1918 pandemic H1N1 influenza strain polymerase complex and identify sensitive sites interfering with polymerase activity in vitro.
- Jeremy R. Keown
- , Zihan Zhu
- & Jonathan M. Grimes
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Article
| Open AccessStructural basis of BAK activation in mitochondrial apoptosis initiation
The authors show that the mechanism of BAK activation in mitochondrial apoptosis involves cooperation between direct activation by BH3-only protein BID and BAK autoactivation, providing a unifying basis for BAK triggering by BH3 ligands.
- Geetika Singh
- , Cristina D. Guibao
- & Tudor Moldoveanu
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Article
| Open AccessA small RNA that cooperatively senses two stacked metabolites in one pocket for gene control
Riboswitches contain an aptamer domain that recognizes a metabolite and an expression platform that regulates gene expression. Here the authors report the crystal structure of a preQ1-sensing riboswitch from Carnobacterium antarcticus that shows two metabolites in a single binding pocket.
- Griffin M. Schroeder
- , Chapin E. Cavender
- & Joseph E. Wedekind
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Article
| Open AccessNeutron crystallography reveals mechanisms used by Pseudomonas aeruginosa for host-cell binding
Pseudomonas aeruginosa employs lectins to bind to its host cells, and is known to be the major cause of lung infections. Lectin B (LecB) from Pseudomonas aeruginosa binds specifically to galactose and fucose and is important for pathogenicity, adhesion and biofilm formation. In this work, the neutron crystal structure (1.9 Å) of the deuterated LecB/Ca/fucose complex is reported. The structure, in combination with perdeuteration of the ligand and the receptor allowed the observation of hydrogen atoms, protonation states and hydrogen bonds involved in the interaction between pathogenic bacteria and host cells. Thus the study provides structural insights into the mechanism of high affinity binding of LecB to its targets.
- Lukas Gajdos
- , Matthew P. Blakeley
- & Anne Imberty
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Article
| Open AccessDesign principles for site-selective hydroxylation by a Rieske oxygenase
SxtT and GxtA are Rieske oxygenases that are involved in paralytic shellfish toxin biosynthesis and catalyze monohydroxylation reactions at different positions on the toxin scaffold. Here, the authors present crystal structures of SxtT and GxtA with the native substrates β-saxitoxinol and saxitoxin as well as a Xenon-pressurized structure of GxtA, which reveal a substrate access tunnel to the active site. Through structure-based mutagenesis studies the authors identify six residues in three different protein regions that determine the substrate specificity and site selectivity of SxtT and GxtA. These findings will aid the rational engineering of other Rieske oxygenases.
- Jianxin Liu
- , Jiayi Tian
- & Jennifer Bridwell-Rabb
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Article
| Open AccessTopoisomerase I (TOP1) dynamics: conformational transition from open to closed states
Topoisomerase I (TOP1) relaxes both positive and negative supercoils by nicking DNA and after rotation of the broken DNA strand closes the nick. Here, the authors present the DNA free crystal structure of TOP1 from the hyperthermophilic archaeon Caldiarchaeum subterraneum in the open form and discuss the mechanism of how DNA enters the catalytic site of TOP1.
- Diane T. Takahashi
- , Danièle Gadelle
- & Claudine Mayer
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Article
| Open AccessCrystal structure and functional implication of bacterial STING
The bacterial Cyclic-oligonucleotide-Based Anti-phage Signaling System (CBASS) contains a CD-NTase that synthesizes cyclic di- and tri-nucleotides, and bacterial STING proteins recognize c-di-GMP generated by CD-NTase during phage infection and signal the infected bacteria to commit suicide. Here, the authors provide insights into the molecular basis for c-di-GMP recognition of bacterial STING proteins by determining two STING protein crystal structures with bound c-di-GMP from Prevotella corporis and Myroides sp. ZB35.
- Tzu-Ping Ko
- , Yu-Chuan Wang
- & Yeh Chen
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Article
| Open AccessCryo-EM structure of native human thyroglobulin
The iodinated thyroglobulin functions as iodine storage and carrier protein and a precursor for thyroid hormone (TH) biogenesis. Here, the authors report the structure of native, fully glycosylated human thyroglobulin, revealing the location of the hTg hormonogenic and glycosylation sites.
- Ricardo Adaixo
- , Eva M. Steiner
- & Nicholas M. I. Taylor
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Article
| Open AccessMicrobial enzymes induce colitis by reactivating triclosan in the mouse gastrointestinal tract
Triclosan (TCS), an antimicrobial agent commonly found in consumer products, has been reported to exacerbates colitis in animal models. Here, using in vitro and in vivo approaches, the authors show that gut bacterial enzymes can drive the metabolic activation and gut toxicity of TCS, highlighting an important role of intestinal microbial factors in the complex etiology of colitis.
- Jianan Zhang
- , Morgan E. Walker
- & Guodong Zhang
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Article
| Open AccessDynamics of GLP-1R peptide agonist engagement are correlated with kinetics of G protein activation
The glucagon-like peptide-1 receptor (GLP-1R) can be targeted in the treatment of diabetes, obesity and other metabolic disorders. Here, the authors assess the molecular mechanisms of peptide agonists binding to GLP-1R and the responses elucidated by these ligands, including distinct kinetics of G protein activation.
- Giuseppe Deganutti
- , Yi-Lynn Liang
- & Denise Wootten
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Article
| Open AccessHarnessing protein folding neural networks for peptide–protein docking
AlphaFold2 has originally been developed to provide highly accurate predictions of protein monomer structures. Here, the authors present a simple adaptation of AlphaFold2 that enables structural modeling of peptide–protein complexes, and explore the underlying mechanisms and limitations of this approach.
- Tomer Tsaban
- , Julia K. Varga
- & Ora Schueler-Furman