Featured
-
-
Article
| Open Access
Structure 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
-
Article
| Open Access
Helical reconstruction of VP39 reveals principles for baculovirus nucleocapsid assembly
Baculoviruses are used as insecticides, gene therapy tools, and protein production vectors. Here, the authors report the structure of the Autographa californica MNPV nucleocapsid and its fold conservation across all baculoviruses.
- Friederike M. C. Benning
- , Simon Jenni
- & Luke H. Chao
-
Article
| Open Access
Remodeling of the ribosomal quality control and integrated stress response by viral ubiquitin deconjugases
Here, the authors show how the vDUB from the large tegument protein from the human herpes virus can reprogram translation in host cells by modulating the activity of the ribosome quality machinery and activating the integrated stress response.
- Jiangnan Liu
- , Noemi Nagy
- & Maria G. Masucci
-
Article
| Open Access
Identification of motif-based interactions between SARS-CoV-2 protein domains and human peptide ligands pinpoint antiviral targets
In this work, the authors mapped putative interactions between protein domains encoded by the SARS-CoV-2 and intrinsically disordered regions of the human proteome. From the data, peptides with antiviral properties targeting Nsp9 and Nsp16 were identified.
- Filip Mihalič
- , Caroline Benz
- & Ylva Ivarsson
-
Article
| Open Access
Multidisciplinary studies with mutated HIV-1 capsid proteins reveal structural mechanisms of lattice stabilization
The effects of E45A or P38A capsid mutations on HIV core stability and infectivity are reversed by R132T or T216I. Here, authors used structural and biophysical methods to reveal short- and long-range rearrangements that explain stability changes.
- Anna T. Gres
- , Karen A. Kirby
- & Stefan G. Sarafianos
-
Article
| Open Access
Structural basis for receptor binding and broader interspecies receptor recognition of currently circulating Omicron sub-variants
SARS-CoV-2 Omicron variant evolves into multiple sub-variants. Here, authors evaluate the binding capacity of these sub-variants to human and animal ACE2s and reveal molecular bases for their receptor binding and broader interspecies recognition.
- Zhennan Zhao
- , Yufeng Xie
- & Jianxun Qi
-
Article
| Open Access
Atomic structure of a nudivirus occlusion body protein determined from a 70-year-old crystal sample
Viral occlusion bodies are robust protein crystals that encapsulate virions of some insect viruses. Here, the authors determine the nudivirus occlusion body structure and describe common principles of occlusion body structure.
- Jeremy R. Keown
- , Adam D. Crawshaw
- & Jonathan M. Grimes
-
Article
| Open Access
Structure of engineered hepatitis C virus E1E2 ectodomain in complex with neutralizing antibodies
HCV vaccine development has been challenged by difficulties in the biochemical preparation of E1E2 ectodomains. Here, the authors structurally characterize an engineered soluble E1E2 ectodomain complexed with broadly neutralizing antibodies, revealing it adopts a native fold amenable for vaccine design.
- Matthew C. Metcalf
- , Benjamin M. Janus
- & Gilad Ofek
-
Article
| Open Access
Structures of active Hantaan virus polymerase uncover the mechanisms of Hantaviridae genome replication
Hantaan virus is a lifethreatening Bunyavirus. Here the authors determine the cryoelectron microscopy structure of its polymerase, a central enzyme involved in viral genome replication. Structures combined with in vitro activity decipher at high resolution the molecular mechanisms of the replication cycle.
- Quentin Durieux Trouilleton
- , Sergio Barata-García
- & Hélène Malet
-
Article
| Open Access
Large-scale phage-based screening reveals extensive pan-viral mimicry of host short linear motifs
Protein-protein interactions underlie all aspects of a viral infection. Here the authors employ a pan-viral approach for systematic identification of motif-mediated interactions between viral and human proteins and show that the information can be used to find targets for antiviral drug development.
- Filip Mihalič
- , Leandro Simonetti
- & Ylva Ivarsson
-
Article
| Open Access
Structural basis of HIV-1 maturation inhibitor binding and activity
HIV maturation inhibitors such as bevirimat (BVM) interfering with Gag processing are emerging as alternative anti-retroviral drug candidates. Here, the authors report structures of assemblies of HIV-1 Gag fragments spanning the CA C-terminal domain and SP1 region bound to BVM.
- Sucharita Sarkar
- , Kaneil K. Zadrozny
- & Tatyana Polenova
-
Article
| Open Access
The ϕPA3 phage nucleus is enclosed by a self-assembling 2D crystalline lattice
To protect from host attack, numerous jumbo bacteriophages establish a micron-scale, protein-based structure to enclose their replicating DNA. Using cryoEM, the authors show that the 2D crystal enclosing this so-called phage nucleus is an assembly of tetramers linked by flexible loops and tails.
- Eliza S. Nieweglowska
- , Axel F. Brilot
- & David A. Agard
-
Article
| Open Access
CryoEM structure and assembly mechanism of a bacterial virus genome gatekeeper
Numerous viruses use a portal system for dsDNA entry and exit from their capsid. Here the authors report the atomic structure of phage SPP1 portal DNA gatekeeper and its mechanism of assembly. They also identify evolution breakpoints between different tailed bacteriophages morphotypes and herpesviruses.
- Igor Orlov
- , Stéphane Roche
- & Elena V. Orlova
-
Article
| Open Access
Omicron SARS-CoV-2 mutations stabilize spike up-RBD conformation and lead to a non-RBM-binding monoclonal antibody escape
The SARS-CoV-2 Omicron variant spreads rapidly. Here the authors show that Omicron S preferentially adopts the one-RBD-up conformation, which leads to a non-RBM-binding monoclonal antibody escape. Mutagenesis reveals that S371L, S373P and S375F substitutions enhance the conformational stability.
- Zhennan Zhao
- , Jingya Zhou
- & George F. Gao
-
Article
| Open Access
Defining the substrate envelope of SARS-CoV-2 main protease to predict and avoid drug resistance
The authors determined crystal structures of the main protease (Mpro) of SARS-CoV-2 bound to substrate peptides. These structures define the substrate envelope and enable identification of sites that may be susceptible to drug resistance.
- Ala M. Shaqra
- , Sarah N. Zvornicanin
- & Celia A. Schiffer
-
Article
| Open Access
A cryptic pocket in Ebola VP35 allosterically controls RNA binding
Many viral proteins are thought to be unlikely candidates for drug discovery as they lack obvious drug binding sites. Here, the authors use computational approaches followed by experimental validation to identify a cryptic pocket within the Ebola virus protein VP35.
- Matthew A. Cruz
- , Thomas E. Frederick
- & Gregory R. Bowman
-
Article
| Open Access
Insights 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
-
Article
| Open Access
Assembly 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
-
Article
| Open Access
Structural basis for SARS-CoV-2 Delta variant recognition of ACE2 receptor and broadly neutralizing antibodies
Here the authors reveal conformational dynamics of SARS-CoV-2 Delta spike and its complex with ACE2 receptor or broadly neutralizing Mab 8D3 by cryo-EM, shedding new insights into mechanisms of receptor recognition and antibody neutralization for the Delta variant.
- Yifan Wang
- , Caixuan Liu
- & Yao Cong
-
Article
| Open Access
Structural 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
-
Article
| Open Access
Structure of HIV-1 Vpr in complex with the human nucleotide excision repair protein hHR23A
Vpr is a HIV-1 accessory virulence factor that also interacts with the human DNA repair protein hHR23A. Here, the authors present the structure of Vpr in complex with the C-terminal half of hHR23A comprising the XPC-binding and ubiquitin-associated domains, which reveals that hHR23A interacts with the DCAF1-binding and not the substrate-binding Vpr surface and further illustrates how Vpr acts as a versatile structural adapter that targets diverse DNA repair pathways.
- In-Ja L. Byeon
- , Guillermo Calero
- & Angela M. Gronenborn
-
Article
| Open Access
Distinct conformations of the HIV-1 V3 loop crown are targetable for broad neutralization
The V3-crown of the HIV-1 envelope protein largely elicits non-neutralizing antibodies. Here, the authors show that the V3-crown can be targeted by broadly neutralizing designed ankyrin repeat proteins recognizing two conformations one of which resembles CCR5- bound V3.
- Nikolas Friedrich
- , Emanuel Stiegeler
- & Alexandra Trkola
-
Article
| Open Access
Molecular insights into receptor binding of recent emerging SARS-CoV-2 variants
The SARS-CoV-2 spike (S) protein mediates viral entry by binding of its receptor-binding domain (RBD) to the human angiotensin-converting enzyme 2 (ACE2) receptor and mutations of the S protein may have a great impact on virus transmissibility. Here, the authors characterize the interactions of six different SARS-CoV-2 RBD variants among them Alpha, Beta and Gamma and present crystal structures of these ACE2-RBD complexes.
- Pengcheng Han
- , Chao Su
- & Jianxun Qi
-
Article
| Open Access
Multianalyte serology in home-sampled blood enables an unbiased assessment of the immune response against SARS-CoV-2
Here, Roxhed et al. develop a multiplexed approach to screen IgG and IgM levels against several SARS-CoV-2 proteins in home-sampled dried blood spots and estimate seroprevalence of 12.5% in Stockholm in spring of 2020.
- Niclas Roxhed
- , Annika Bendes
- & Jochen M. Schwenk
-
Article
| Open Access
Cryo-EM structures of HIV-1 trimer bound to CD4-mimetics BNM-III-170 and M48U1 adopt a CD4-bound open conformation
Conformational changes of HIV’s Env protein are required for its function in fusing the viral and host cell membranes. Here the authors describe how two small molecules alter the confirmation of Env trimers, and show they can induce structural changes similar to those occur upon receptor binding.
- Claudia A. Jette
- , Christopher O. Barnes
- & Pamela J. Bjorkman
-
Article
| Open Access
Hierarchized phosphotarget binding by the seven human 14-3-3 isoforms
14-3-3 proteins recognize phosphorylated motifs within numerous protein partners. Here, the authors characterize the binding of all human 14-3-3 isoforms to four E6 oncoproteins, and identify a fixed order of 14-3-3 binding affinities that is conserved in 14-3-3:phosphoprotein interactions across the proteome.
- Gergo Gogl
- , Kristina V. Tugaeva
- & Nikolai N. Sluchanko
-
Article
| Open Access
Stabilizing the closed SARS-CoV-2 spike trimer
SARS-CoV-2 S protein prematurely refolds to the post-fusion conformation, compromising immunogenic properties and prefusion trimer yield. Here, Juraszek et al. present a stable SARS-CoV-2 S-closed protein variant with increased expression and correct folding, predominantly in closed prefusion conformation.
- Jarek Juraszek
- , Lucy Rutten
- & Johannes P. M. Langedijk
-
Article
| Open Access
Establishing a mass spectrometry-based system for rapid detection of SARS-CoV-2 in large clinical sample cohorts
Large population testing is a key step to controlling the COVID-19 pandemic. Here, the authors develop a targeted mass spectrometry system for peptide-based SARS-CoV-2 detection, allowing analysis of over 500 swab samples per day and enabling virus detection even after prolonged sample storage at room temperature.
- Karina Helena Morais Cardozo
- , Adriana Lebkuchen
- & Valdemir Melechco Carvalho
-
Article
| Open Access
Viral Bcl2s’ transmembrane domain interact with host Bcl2 proteins to control cellular apoptosis
Viral analogs of B-cell lymphoma 2 (Bcl2), known as vBcl2s, control apoptosis by interacting with host pro- and anti-apoptotic members of the Bcl2 family. Here, García-Murria et al. report on transmembrane domains (TMDs) in the C-terminal hydrophobic region of herpes- and poxviral vBcl2s, which mediate homo-oligomerization and interactions with cellular Bcl2 TMDs to control apoptosis.
- Maria Jesús García-Murria
- , Gerard Duart
- & Luis Martínez-Gil
-
Article
| Open Access
Rapid incorporation of Favipiravir by the fast and permissive viral RNA polymerase complex results in SARS-CoV-2 lethal mutagenesis
Favipiravir (T-705) is an inhibitor of viral RNA-dependent-RNA-polymerases (RdRp) and clinical trials for the treatment of COVID-19 are ongoing. Here, the authors show that SARS-CoV nsp12 is the fastest known viral RdRp and they provide insights into the mechanism of action of Favipiravir, demonstrating that its antiviral effect on SARS-CoV-2 is primarily mediated through lethal mutagenesis.
- Ashleigh Shannon
- , Barbara Selisko
- & Bruno Canard
-
Article
| Open Access
Dynamic remodelling of the human host cell proteome and phosphoproteome upon enterovirus infection
Here, Giansanti et al. perform a system-wide and time-resolved characterization of the changes in the host cell proteome and phosphoproteome of cells infected with the enterovirus coxsackievirus B3 during a full round of replication and identify mTORC1 signalling as a major regulation network during virus infection.
- Piero Giansanti
- , Jeroen R. P. M. Strating
- & Frank J. M. van Kuppeveld
-
Article
| Open Access
Pre-initiation and elongation structures of full-length La Crosse virus polymerase reveal functionally important conformational changes
RNA-dependent RNA polymerases from segmented negative stranded RNA viruses catalyze genome replication and viral transcription. Here, the authors present the cryo-EM structure of full-length La Crosse virus polymerase and structurally characterize the pre-initiation and elongation states, which is of interest for the development of polymerase inhibitors.
- Benoît Arragain
- , Grégory Effantin
- & Hélène Malet
-
Article
| Open Access
SARS-CoV-2 proteome microarray for global profiling of COVID-19 specific IgG and IgM responses
Currently very little is known about how our immune system responds to SARS-CoV-2 infection. Here the authors generate a SARS-CoV-2 proteome microarray for profiling of IgG and IgM responses to COVID-19 in patients and find significant responses to ORF9b and NSP5, as well as the S1 and N proteins.
- He-wei Jiang
- , Yang Li
- & Sheng-ce Tao
-
Article
| Open Access
Rational design of a multi-valent human papillomavirus vaccine by capsomere-hybrid co-assembly of virus-like particles
An effective vaccine for human papillomavirus (HPV) needs to protect from several genotypes. Here, Wang et al. provide a strategy to produce single capsomere-hybrid virus-like particle (chVLP) composed of capsomers of different genotypes and show that a nona-type chVLP induces similar levels of neutralizing antibodies as an approved HPV vaccine.
- Daning Wang
- , Xinlin Liu
- & Shaowei Li
-
Article
| Open Access
Structural basis for Fullerene geometry in a human endogenous retrovirus capsid
In retroviruses, the capsid protein (CA) forms a shell surrounding the viral core. Here the authors combine cryo-electron microscopy with NMR and X-ray crystallography to examine the CA structure from the human endogenous retrovirus HML2 (HERV-K) and determine the structures of four Fullerene CA closed shells that reveal the molecular basis of capsid assembly.
- Oliver Acton
- , Tim Grant
- & Peter B. Rosenthal
-
Article
| Open Access
A second open reading frame in human enterovirus determines viral replication in intestinal epithelial cells
The majority of enterovirus proteins are encoded as polyprotein in one open reading frame. Here, Guo et al. characterize a second open reading frame in human enteroviruses and show that it is important for viral particle release, particularly in epithelial cells, and that it affects mortality in a mouse model.
- Haoran Guo
- , Yan Li
- & Wei Wei
-
Article
| Open Access
A post-translational modification of human Norovirus capsid protein attenuates glycan binding
Attachment of human noroviruses to histo blood group antigens (HBGAs) is essential for infection. Here the authors report that an asparagine residue located near the HBGA-attachment site can convert into an iso-aspartate residue through spontaneous deamidation and influence HBGA recognition.
- Alvaro Mallagaray
- , Robert Creutznacher
- & Thomas Peters
-
Article
| Open Access
Orthobunyavirus spike architecture and recognition by neutralizing antibodies
Orthobunyaviruses (OBVs) cause severe disease in humans and farm animals, but the molecular basis for infection is not fully understood. Here, the authors present crystal structures of free and antibody-bound OBV envelope glycoproteins and show that their domains enable efficient immunization in a mouse model.
- Jan Hellert
- , Andrea Aebischer
- & Félix A. Rey
-
Article
| Open Access
Nucleotide-dependent DNA gripping and an end-clamp mechanism regulate the bacteriophage T4 viral packaging motor
Packaging of viral DNA depends on strong molecular motors that are powered by ATP hydrolysis. Here, the authors develop a single-molecule assay to monitor how nucleotide binding regulates motor-DNA interactions and reveal a generic mechanism that prevents exit of the whole DNA from the viral capsid during packaging.
- Mariam Ordyan
- , Istiaq Alam
- & Douglas E. Smith
-
Article
| Open Access
Quantitative characterization of all single amino acid variants of a viral capsid-based drug delivery vehicle
Self-assembling proteins have important applications in industrial technologies, but it is difficult to predict how mutations affect assembly. Here the authors present SyMAPS, coupling comprehensive codon mutagenesis with high-throughput sequencing, and apply it to bacteriophage capsid protein.
- Emily C. Hartman
- , Christopher M. Jakobson
- & Danielle Tullman-Ercek
-
Article
| Open Access
Structural basis for the recognition of LDL-receptor family members by VSV glycoprotein
Glycoprotein G of vesicular stomatitis virus (VSV) enables viral entry by binding to the major VSV receptor LDL-R. Here the authors present crystal structures of G in complex with two distinct CR domains of LDL-R, identifying structural determinants for VSV infectivity in mammalian and insect cells.
- Jovan Nikolic
- , Laura Belot
- & Aurélie A. Albertini
-
Article
| Open Access
Adenoviral vector with shield and adapter increases tumor specificity and escapes liver and immune control
Viral gene therapy can be limited by the efficacy of virion sequestration, immune responses and the silencing of genetic payloads. Here the authors engineer an advenovirus protein coat which shields the virion from the immune system while targeting cancer cells.
- Markus Schmid
- , Patrick Ernst
- & Andreas Plückthun
-
Article
| Open Access
Physical properties of the HIV-1 capsid from all-atom molecular dynamics simulations
The large and complex HIV-1 capsid modulates several molecular events during HIV-1’s infective cycle. Here the authors use all-atom molecular dynamic simulations to probe the biophysical properties of the genome-free HIV-1 capsid.
- Juan R. Perilla
- & Klaus Schulten
-
Article
| Open Access
Idiosyncratic Mòjiāng virus attachment glycoprotein directs a host-cell entry pathway distinct from genetically related henipaviruses
The attachment glycoprotein (HNV-G) of henipaviruses interacts with host receptors at the cell surface and is a major determinant of species tropism. Here the authors provide structural and functional evidence that the emergent henipavirus, Mòjiang virus, uses an entry mechanism that is independent of known paramyoxviral cellular receptors.
- Ilona Rissanen
- , Asim A. Ahmed
- & Thomas A. Bowden
-
Article
| Open Access
Portal protein functions akin to a DNA-sensor that couples genome-packaging to icosahedral capsid maturation
Tailed bacteriophages assemble empty precursor capsids known as procapsids that are subsequently filled with viral DNA by a genome-packaging motor. Here the authors present a structure-based analysis that suggests the signal for termination of genome packaging is achieved through a DNA-dependent symmetrization of portal protein.
- Ravi K. Lokareddy
- , Rajeshwer S. Sankhala
- & Gino Cingolani
-
Article
| Open Access
Long noncoding RNA NRON contributes to HIV-1 latency by specifically inducing tat protein degradation
Long noncoding RNAs have a wide range of physiological functions, though their role in viral infection and latency is poorly understood. Here the authors show a lncRNA NRON can induce degradation of HIV-1 protein Tat, potentially contributing to latent infection.
- Jun Li
- , Cancan Chen
- & Hui Zhang
-
Article
| Open Access
Specifically modified Env immunogens activate B-cell precursors of broadly neutralizing HIV-1 antibodies in transgenic mice
The induction of broadly neutralizing antibodies (bNAbs) is a goal of HIV-1 vaccine research. Here the authors demonstrate the ability of an HIV Env-derived immunogen to bind germline precursors of a class of bNAbs and to activate the corresponding B cells in a knock-in mouse model
- Andrew T. McGuire
- , Matthew D. Gray
- & Leonidas Stamatatos
-
Article
| Open Access
X-ray structure and activities of an essential Mononegavirales L-protein domain
TheMononegaviralesinclude Ebola virus, Rabies, Measles virus and human Metapneumovirus (hMPV). Here, the authors have reported the high resolution crystal structure of a domain of the large protein of hMPV, providing insight into the mRNA modifying activities of this protein.
- Guido C. Paesen
- , Axelle Collet
- & Jonathan M. Grimes
-
Article |
Inhibition of Ebola virus glycoprotein-mediated cytotoxicity by targeting its transmembrane domain and cholesterol
The GP protein of the Ebola virus is involved in the detachment of infected cells, which eventually leads to vascular leakage and contributes to haemorrhagic fever. Here Hacke et al.show that the membrane-anchored subunit of GP is sufficient to induce cell detachment, and that cholesterol contributes to this process.
- Moritz Hacke
- , Patrik Björkholm
- & Andreas M. Ernst
Structural characterization of the oligomerization of full-length Hantaan virus polymerase into symmetric dimers and hexamers